The Human Immunodeficiency Virus type 1 (HIV-1) is unlike any virus that medicine has ever encountered.  Since its discovery in the United States about 20 years ago, it has infected an estimated 40 million individuals (1), and of those people more than 16.3 million have died of AIDS (2).  There are now a few different types of therapies available to combat the virus.  This paper will focus on three of these.  However, before discussion begins on therapeutic measures, one must have a basic scientific background on HIV-1 and how it works.  Therefore this paper will begin with a necessarily small amount of information regarding the virus, its biochemistry and genetics, and how it evades killing by the host’s immune system.  Then, three combative methods will be introduced.  First, the current line-up of antiviral drugs and some projects under investigation will be examined.  Second, an array of different types of vaccine schemes will be discussed.  Third, this paper will look at some of the psychological effects of HIV/AIDS and the methods by which clinicians are reacting to them.

Like all viruses, HIV-1 is an intracellular parasite.  In other words, without the host cell, the virus cannot multiply.  HIV-1 must find its way to a host cell, attach to the cell=s surface, then insert itself into the cytoplasmic matrix, integrate its genome into the host=s DNA and make copies of itself.  All viruses differ in the method by which they accomplish infection.  In order to see how HIV-1 does this one must have some information about the biochemical and genetic makeup of the virus.  HIV-1 is a double-stranded RNA (dsRNA) virus that belongs to the family Retroviridae (1).  A single virion has a spherical shape with a knobby-looking envelope.  The knobs are comprised of the envelope glycoproteins gp120 and gp160.  These two glycoprotein surface antigens will be discussed more in depth later as they form the target of attack for vaccine therapies.  Just beneath the envelope is the viral matrix which, aside from structural maintenance, enables the DNA copy of the viral genome to be transmitted to the host nucleus.   Inside this is the capsid.  This structure contains two identical strands of dsRNA, and the enzymes protease, integrase, and reverse transcriptase (RT).  The viral genome is relatively simple.  It consists of nine genes: gag, pol, env, tat, rev, nef, vif, vpu, and vpr (1). 

Like all viruses, HIV-1 needs a host cell to proliferate itself.  Research has indicated that HIV-1 will only infect human cells that bear a CD4 surface marker (3).  These cells include macrophages, some dendritic cells, and, most importantly, CD4+ T-lymphocytes.  The virus will attach its gp120 surface protein to the V_α and V_β variable regions of the CD4 receptor (4) and the CCR-2, CXCR-5, and CXCR-4 co-receptor molecules (5,6).  The viral envelope then fuses with the host plasma membrane and allows penetration by the capsid.  The RT then copies the dsRNA genome to a dsDNA form.  This transformation takes place in three types of reactions:  RNA directed DNA synthesis, DNA directed DNA synthesis (both carried out by the polymerase moiety of RT), and RNA hydrolysis (directed by RNAse H) (7).  The dsDNA and integrase insert into the host cell’s nucleus and are incorporated into the host chromosome.  The viral DNA is then known as a provirus.  This provirus then begins the genetic work of producing new virions.  The env gene encodes gp120 and gp41 (a transmembrane protein that anchors gp120).  The gag gene codes for certain nucleocapsid core proteins such as p24 (the capsid protein) and p17 (the matrix protein).  The pol gene is very important as it codes for RT, RNAse H, integrase, and protease (all of which are included on a single polyprotein) (6).  The genes tat, rev, nef, vif, and vpu are regulatory and serve various functions such as transcriptional activation, structural gene expression, virion budding, and infectivity promotion (8).  The auxiliary gene vpr improves efficiency of replication (6).  After all nine genes are transcribed and translated, the viral proteins congregate just below the plasma membrane where they assemble themselves into new capsids.  The envelop proteins are previously transported to the nearby membrane by the golgi apparatus.  As the capsid buds out of the host cell, part of the plasma membrane clings to it and becomes the viral envelope.  Shortly thereafter, the viral protease cleaves the pol polyprotein and the HIV-1 particle is now a mature, infective virion.  As one can see, this genetic infiltration and subsequent protein synthesis stresses the host CD4+ T-lymphocyte.  As the host cell produces thousands of viral copies per day, it is eventually weakened and then dies.  Additionally, the viral antigens are processed and presented in the usual fashion and thus CD-4 cells are also killed by other immune cells such as cytotoxic T-cells and natural killer cells.  It is a blood CD4 cell count of <200H10⁶/L that defines advanced AIDS.  Despite normal antigen processing and presentation, HIV-1 has two mechanisms that make it very adept at evading the immune system: mutability and latency.

A defining feature of retroviruses is their tendency to undergo rapid and frequent genetic mutation.  The most important reason for this is that reverse transcriptase is relatively inefficient compared to mammalian DNA polymerase.  This inherent defect leads to many base-pair mismatches and point mutations.  Combined with a high viral replication rate, these mistakes can give rise to an estimated 100 million mutant viruses per day (9).  This mutability is a very large problem as the mutations are most often manifested as changes in the surface proteins (9,10).  Therefore, because of the great specificity in recognizing antibodies, the always changing surface antigens facilitate immune system evasion by the virus.  Another method by which HIV-1 avoids immune system destruction is by using its ability to regulate its self production and therefore remain latent for years in living cells.

Recent studies suggest that in addition to latency and mutability, the virus has yet another method for immune evasion.  It has been suggested that HIV can induce a state of T cell receptor (TCR) mediated anergy.  Anergy is defined as Athe loss or weakening of an immune response to an irritating agent or antigen (1).@  Normally when a virus is introduced into the host system, it is recognized as foreign and is taken up by professional antigen presenting cells (APCs).  The APC will degrade the virus particle and will present short viral peptides, usually 9-14 amino acids in length, in conjunction with major histocompatibility complex (MHC) class II molecules on its surface.  A specific T cell then recognizes these short fragments and links its TCR to the APC=s MHC class II surface molecule.  This TCR/MHC linkage sets off a chain of biochemical events that will stimulate the T lymphocyte to secrete a cytokine called interleukin-2 (IL-2).  The immune system is very specific and T cell stimulation with an antigen that varies from the native peptide structure by as little as one amino acid can result in induction of anergy.  The affected lymphocyte will now not produce IL-2 in response to an antigen even if it is presented with the correct one (9).  IL-2 is very important as it is a growth factor for T helper type 1 cells.  Without these cells, the host cannot initiate a cell-mediated immune response.

Thus far, this paper has discussed a small portion of what is the biochemistry and genetics of HIV-1, how the virus infects CD4 cells, how it replicates, and how it evades destruction by the host’s immune system.  The focus shall now turn to three methods by which clinicians treat HIV-1 infection and its subsequent progression to AIDS.

Ever since the isolation of HIV, drug manufacturers have been scrambling to come up with effective treatments.  There are now three FDA approved classes of drugs available for the treatment of HIV/AIDS.  The first to be discovered and implemented were the nucleoside reverse transcriptase inhibitors (NRTIs).  The second class to be found effective was the nonnucleoside reverse transcriptase inhibitors (NNRTIs).  The final class of drugs to be approved was the protease inhibitors (PIs) (11).  Each class works in its own specific way and will be discussed in turn.

On September 17, 1986, a new drug was approved by the FDA.  The drug, a thymidine analog called azidothymidine (AZT), was the first substance to show efficacy in fighting HIV.  The effectiveness of AZT lasted only a brief time but spawned a host of other related drugs such as ddI, d4T, ddC, Abacavir, and 3TC.  Collectively, these drugs are called nucleoside reverse transcriptase inhibitors (NRTIs).  They all work by a similar method which is to mimic the building blocks of DNA and thereby inhibit replication of the HIV virion by terminating DNA chain elongation (12).  Each of these drugs is an analog of a different nucleoside.  They are therefore competitive enzyme inhibitors.  AZT is a thymidine mimic, ddI is an analog of adenosine, 3TC and ddC mimic cytidine, and Abacavir is an analog for guanosine (13).   Upon take-up by the host cells, the drugs are phosphorylated by nucleotide kinase thereby converting them to the active nucleotide form.

The next class of drugs is the nonnucleoside reverse transcriptase inhibitors (NNRTIs).  These drugs, such as nevirapine, delavirdine, and efavirenz, achieve the same end and the NRTIs (inhibition of RT), but their mechanism of action differs.  As they are nonnucleosides, they do not bind to the active site of RT, but bind remotely and hence are non-competitive enzyme inhibitors. Also because of these differences, viral resistance mechanisms are also different.  Because of this, while neither class of drug is very effective individually, taken in combination, the NRTIs and NNRTIs have demonstrated excellent viral load reduction in patients.  Significant to note also is that nervirapine is able to cross the blood-brain barrier and thus get at virus concentrations contained in the dendritic cells of the central nervous system (13).

            The third and final group of FDA approved drugs is the protease inhibitors (PIs).  HIV protease is an aspartyl protease enzyme similar to mammalian proteases like renin, but is specific for HIV proteins and does not cross react with human proteases (14).  As mentioned previously, the HIV protease cleaves the pol polyprotein shortly after viral budding.  The effect of this cleavage is to activate RT, RNAse H, integrase, and protease itself.  This completes the life cycle of HIV-1 and without this step cannot infect new CD4 cells.  These drugs, indinavir, nelfinavir, ritonavir, and the 2^nd generation saquinavir (Invirase) are much more powerful than the other two classes of medications.  They have been shown to reduce viral load by as much as 99% (15).

Given all of this drug information, one would perhaps have the question of when to use these drugs and, if their use is warranted, how to prescribe them properly.  There are some guidelines that have been established along the lines of when should a clinician treat the disease and when he should defer treatment.  Generally, treatment is deferred only in patients that still have a high CD4 cell count (>500x10⁶/L) and a low viral load (<5000 RNA copies/mL).  Otherwise treatment is implemented (16).  However, one should realize that anti-HIV drugs are not effective when used by themselves.  For maximal efficiency, the medications must be combined in to a regimen called highly active antiretroviral therapy or HAART.  If the decision is made to go ahead with treatment, the current recommended combinations are: one PI and two NRTIs, (such as indinavir plus d4T and ddI) or one NNRTI and two NRTIs (such as Efavirenz plus d4T and 3TC).  However, d4T should not be used with AZT, and ddC should not be combined with 3TC, d4T, or ddI.  All other NRTI combinations have been deemed safe (JHH).  One NNRTI plus two NRTIs is effective, but the regimen of one PI plus two NRTIs has historically been judged the most efficacious and longest lasting (17).  However, caution is warranted when combining PIs with NNRTIs or some other drugs used to treat AIDS specific diseases.  PIs and NNRTIs are both metabolized hepatically by the cytochrome P-450 system (13).  This can cause cross reactions that are sometimes fatal (16).  Physicians and patients also must be careful about mixing PIs and certain antibiotics (ciprofloxacin, enoxacin, isoniazid, cycloserine, various antifungals), antihistamines, SSRI antidepressants (prozac etc.), and contraceptives containing ethinyl estradiol.

However, in recent years, physicians and patients have witnessed increasing rates of treatment failures when using two NRTIs and one PI.  Up to 50% of patients experience virologic failure after 12 months of this type of treatment (18).  Therefore, research and trials have begun using a four drug “salvage regimen” of two NRTIs and a PI combination of ritonavir (or nelfinavir) and saquinavir.  In one study, PI naïve patients were given either ritonavir 600 mg b.i.d. or ritonavir 600 mg b.i.d. and saquinavir 400 mg b.i.d.  All of the patients had previously received an average of 42 months of treatment with two NRTIs, and had a baseline viral load average of 4.75 log₁₀ copies/mL.  At the end of 24 weeks, viral load in patients receiving ritonavir alone was 2.81 log₁₀ copies/mL.  In those patients taking the ritonavir-saquinavir combination, viral load was 2.08 log₁₀ copies/mL.  These significant differences remained until the end of the 48 week study (19).  Similar research has carried the time frame for this type of therapy further and demonstrated that after 3.3 years of therapy using ritonavir-saquinavir and two NRTIs, only 25.3% of patients experienced viral rebound.  And much of this was due to therapy interruption and other non-compliance (20).  One may wonder why the two PI regimen is so much more effective than the single method.  The reasons lie in plasma drug levels and genotypic resistance (21).  It has been found that plasma levels of saquinavir are increased substantially when administered with either ritonavir or nelfinavir.  This has been correlated with increased viral toxicity (22).  Also, increased bioavailability allows patients to take the drugs less often and in smaller doses.  This can help lessen side effects and makes the medications more convenient and thus increases treatment adherence.   More importantly, however, is the effect that dual PIs have on genetic mutations.  The presence of the common L90M core mutation is highly correlated with decreased effectiveness of PIs in general.  In one study, six patients who were taking ritonavir alone developed aL90M protease mutation compared to one patient taking the ritonavir-saquinavir regimen (19).  Research by Casado has proven that fewer protease mutations means higher virologic response.  In his study, 62 HIV positive patients in virologic failure were evaluated.  At the beginning of the study, the median HIV RNA level was 4.78 log₁₀ copies/mL; the median number of protease mutations was nine.  At the end of twelve weeks, patients with three or fewer protease mutations showed a viral load decrease of 2.13 log₁₀ copies/mL, as compared with a decrease of 0.48 log₁₀ copies/mL in patients whose viruses had 11 or more mutations.  As has been shown, various combinations of these well established drugs have been proven to effectively reduce viral load while minimizing toxic side effects (which even now are still very problematic) and reduce viral resistance to any one medication.

While the current crop of anti-HIV medications are proving effective at prolonging life, HIV/AIDS is still very much a terminal illness and, therefore, research into new treatment methods are ongoing.  The next section will discuss certain new types of therapies under study and also some methods to increase the effectiveness of drugs already available.

As with many medications, anti HIV drugs target the metabolic processes that the virus uses to reproduce itself.  However, the “ultimate parasite” (6) relationship between the virion and the host cell is extremely intertwined.  This fact makes development of new drugs extraordinarily difficult as the compound must specifically inhibit essential components of the virus’ biochemistry without damaging the host cell beyond repair.  All of the aforementioned drugs do just this.  However, to fully combat HIV and hopefully achieve the goal of curing the disease, researchers are tirelessly endeavoring to find new and interesting methods by which to attack the virus.  This paper will introduce four: 4’ ethynyl nucleoside analogs, pyrrolobenzoxazepinones, TXU-PAP conjugates, and fullerenes.  As NRTIs, NNRTIs, and PIs are the current state of anti HIV medications, perhaps one or more of these new experimental substances will be the future.

The 4’-ethynyl (4’-E) nucleoside analogs have much in common with the current crop of NRTIs such as zidovudine.  The only chemical difference (on the ribose anyway) is that the 4’-E nucleosides have ethynyl substitutions at the 4’ position of the sugar moiety (23) instead of the varied 3’ substitutions found in other NRTIs (3’-N₃ in AZT for instance) (24).  Besides the obvious differences in the nitrogenous base attached, the 4’ and 3’ positions on the ribose moiety is where all of the NRTIs differ.  The 4’-E analogs are therefore simply one more way to exploit differences in these structural sites.  One recent study looked at the antiviral activity of twenty different 4’-E nucleosides and compared their antiviral activity.  To facilitate the study, lines of MT-4 cells were grown in culture to which different strains of HIV-1 were added at 50% tissue culture infectious doses (TCID₅₀).  Three lab strains, an unknown number of multi-drug resistant clinical isolated strains, and five infectious recombinant clones (with various mutations in the pol gene) were used.  The inhibitory effects of the test compounds were noted by virally induced cytotoxicity in the MT-4 cells.  The results showed that 4’-E-thymidine was active against lab strains.  All four cytidine analogs were active against all strains [most notably 4’-E-2’-deoxycytidine (4’-E-dC)].  Of the purine analogs, 4’-E-2’-deoxyadenosine (4’-E-dA), 4’-E-2’-deoxyribofuranosyl-2,6-diaminopurine (4’-E-dDAP), and 4’-E-2’-deoxyguanosine (4’-E-dG) were the most potent.  4’-E-dDAP and 4’-E-dA were also only minimally toxic to the host cells.  The cytidine analogs were also the most potent of the group against multi-drug resistant strains, most notably ddI/ddC and AZT/ddI/ddC/d4T/3TC resistant types.  The purine analogs 4’-E-dA, 4’-E-dDAP, and 4’-E-dG were additionally active against all recombinant clones tested and also inhibited an NNTRI-resistant clone.  This study found four highly active new compounds: 4’-E-dG, 4’-E-dC, 4’-E-dA, and 4’-E-dDAP.  Of these, the last three (dG, dC, and dDAP) suppressed replication in all infectious clones examined which were resistant to all currently available NRTIs. (23). Results such as these are very promising and research in the area of 4’ substituted nucleosides is ongoing.

On the non-nucleoside end of things, much research has gone into developing a class of drugs called pyrrolobenzoxazepinone (PBO) derivaties.  Like other NNRTIs such as nevirapine, PBOs bind reverse transcriptase at a location removed from the actual active site.  Therefore, they are allosteric enzyme inhibitors.  This type of compound overcomes some of the drawbacks inherent in NRTIs such as AZT.  They are highly specific, exhibit low cytotoxicity, and can cross the blood-brain barrier (25).  A study done in Italy examined the basic PBO and, unsatisfied with its spectrum of action, developed derivatives with increased effectiveness.  This was done by an interesting application of molecular modeling.  Thus, the new PBOs were “custom made” to interact with a very specific site on the RT molecule.  These compounds exhibit low toxicity (TC₅₀>1 mM).  Importantly, two of the group showed synergistic anti-HIV activity when tested in combination with AZT (25).  These two properties suggest potential clinical usefulness when combined with existing NRTIs to combat HIV strains bearing mutations that confer resistance to known NNRTIs.

A contrast to the highly technical development of pyrrolobenzoxazepinones was the discovery of pokeweed antiviral protein (PAP).  In 1974, a group of astute botanists noticed that a ribosome inhibitory protein isolated from Phytolacca americana was able to inhibit the transmission of tobacco mosaic virus in plants (26).  Researchers soon realized that PAP inhibited mammalian viruses as well (27).  PAP is an RNA N-glycosidase that removes an adenine base from a highly conserved area of eukaryotic 28s rRNA.  The removal of adenine at this position results in irreversible inhibition of protein synthesis at the translocation step (28).  Recent studies have shown that PAP is specifically antiviral because it carries out adenine removal, not singly, but extensively on viral RNA (29).  But to have an effect against HIV directly, the substance must be able to enter living cells and stop protein synthesis.  Scientists solved the problem of cellular uptake by conjugating the anti-CD7 immunoglobulin TXU to the antiviral protein.   Having shown effectiveness in inhibiting viral replication, research was designed to compare the TXU-PAP conjugate and AZT both in cell culture and in a SCID mouse model of human AIDS.  Both tests used clinical strains of HIV.  The in vitro assays tested for concentrations of p24 antigen and RT.  In the mouse model, peritoneal lavage and spleen cells were examined for infection.  The studies found that TXU-PAP inhibited HIV in a dose dependent fashion and that unconjugated PAP was 270 to 400 times less effective than the conjugated version (30).  In culture, TXU-PAP inhibited p24 and RT nearly completely and was observed to be 500-1000 times as effective as AZT.  In the mouse model, after the 14 day regimen of 10-20μg, zero of the twenty mice tested remained HIV positive by PCR.  Conversely, only three of ten mice treated with 200mg of AZT per day tested HIV negative.  Notably, the 10-20μg over 14 days dose of TXU-PAP was very well tolerated and the mice showed no adverse side effects (30).  Due to this promising evidence, the same team of researchers began a study to examine low dose TXU-PAP therapy in humans.  The patients they used for this study had all previously failed a regimen including all current methods of treatment.  They found that low dose treatment reduced viral load in all six patients under study, although it did not provide sustained therapeutic plasma levels.  However, one should note that the dose given was 100-fold lower than the established toxic level.  Also favorably, the drug had a long circulating half-life, was very well tolerated (only slight liver enzyme elevation), and, unexpectedly, increased numbers of circulating natural killer cells (29).

The 1996 Nobel Prize in Chemistry was awarded to H.W. Kroto, R.F. Curl, and R.E. Smalley for their discovery of a new allotrope of carbon, C₆₀.  Named buckminsterfullerene, and affectionately called (buckyball), this form of carbon takes a round soccerball-like appearance.  It has been proposed that C₆₀ can be used for many purposes including virus inhibition.  Molecular modeling shows that the buckyball fits nicely into the hydrophobic cavity of HIV protease and has indeed shown antiviral activity in infected cells (31).  The fullerenes show no cytotoxicity up to 100μM and are currently under further study.

The preceding pages have examined some new and sometimes novel ways to combat HIV infection.  The focus will now turn to methods under study to improve the efficacy of drugs that are currently available.

Shortly after the introduction of AZT, physicians began seeing the emergence of viral resistance to this drug.  The majority of HIV strains are now unaffected by this previously powerful compound (13).  There now exists a way to restore its antiviral activity.  Recent research indicates that a certain thiocarboxanilide can act synergistically with AZT to inhibit replication in previously AZT-resistant strains.  If used separately, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide (UC781) and AZT show similar strengths of HIV inhibition.  If used together, the antiviral activity of a 1:1 molar combination was significantly greater than that of either drug singly (32).  This would imply that the function of AZT was restored by the presence if UC781 as little or no synergistic effect was noted with an AZT/nevirapine combination.  Also, the time to resistance development was significantly delayed when the combination was used compared to individual drug use (32).

Some problems with current PIs are that they are metabolized at a very high rate, are expelled from cells by the P-glycoprotein (PgP) transport system, and they bind to plasma proteins (acosta).  All of these factors lower blood concentrations of the drugs.  Therefore, coadministration of low dose ritonavir in conjunction with another PI is currently used to boost the pharmacologic effects of the medications (16).  If researchers can find ways to alter or partially inhibit the aforementioned concentration reducing processes, perhaps drug levels would rise and outcomes would improve.  As stated previously, PIs are metabolized primarily by the 3A4 isozyme of the cytochrome P-450 system.  Ritonavir has been shown to be an active inhibitor of this enzyme and that is the reason that it is sometimes given in concomitantly with other PIs.  If given a combination of indinavir/ritonavir (800mg/100mg, 800mg/200mg, and 400mg/400mg every twelve hours for fourteen days), patients saw a three-fold increase over their previous indinavir levels from a regimen of 800mg every eight hours (33).  The PgP protein is a unique bidirectional cellular counter transport mechanism.  It is able to mediate the efflux of PIs from cells.  All PIs are substrates for this system, but, again, ritonavir has been shown to inhibit this system.  Ritonavir can cause a ten to fifteen fold increase in indinavir and amprenavir levels (33).  There are many proteins in plasma that PIs can bind to, but their primary ligand is [alpha]₁-acid glycoprotein.  Only unbound drug is active and binding to this protein effectively deactivates PIs.  Plasma levels of [alpha]₁-acid glycoprotein vary between patients, but only small increases or decreases in concentration are needed to significantly affect the amount of free drug.  Normal levels can reduce PI concentrations by 60% (33).  There is no current method to reduce protein binding, but research is underway.  One recommendation given in current studies is that physicians should perhaps be more diligent in ascertaining and recording patients’ plasma drug levels.  This would be advantageous in defining optimal therapeutic PI concentrations (33).

Thus far, this paper has looked at some of the chemical aspects of HIV.  Its biochemistry, genetics, and immune system evasion were discussed.  The current set of anti-HIV medications was examined.  Some new advances in therapy as well as methods to increase efficiency of current medications were introduced.  The focus shall now turn to discussion of some research underway to derive a vaccine for HIV.

Since the majority of the cases of HIV-1 erupt in developing countries, the cost of treatment is oftentimes prohibitive.  For these and other reasons, it is apparent that development of a safe, accessible, and inexpensive vaccine is needed to control the further spread of HIV-1.  In addition to being safe and inexpensive, an HIV-1 vaccine must activate both antibody-mediated and cell-mediated immunity.  Many current vaccines in clinical trials are aimed at stimulating antibody production, but the action of only one branch of the immune system is not enough to control the virus.  The entire system may need to be activated in order to prevent infection.  An effective vaccine must produce a strong initial response and remain active for long periods of time.  Lastly, it must be widely cross reactive as to neutralize the many different strains of the virus that exist in the world=s population.  Although much research is being devoted to the cause of finding a vaccine for this unique virus, no method of immunization has yet proven effective.  The purpose of this section is to investigate the HIV-1 virus itself, some aspects of the immune response, and current vaccine types under research.

In addition to drug development, since the identification of HIV-1 as the causative agent of the many symptoms that constitute acquired immunodeficiency syndrome (AIDS), there has been intensive research focused on developing an effective vaccine.  Despite heroic efforts, none has yet been produced.  The inability to synthesize an effective vaccine stems from many unique factors involved in the biology and pathogenicity of the HIV-1 virus.  To understand these we must understand the molecular biology of the virus and the methods by which it avoids attack by the immune system.  These concepts have been dealt with previously (recall mutability, latency, and anergy).  We must also understand the correlates of immunity involved with HIV-1 infection and prevention.  Once these facts are understood, a weakness in the virus may be found and exploited.

Since HIV-1 effectively eliminates most of the CD4 cells in the host, research has been and is being done on ways to reconstitute the immune system.  One method of doing this is by subcutaneous injection of the cytokine interleukin-2 (IL-2).  A study done in July 2000 aimed to ascertain the effect of IL-2 injection and antiretroviral therapy (ART) on the immune system and plasma viral load.  A random group of eighty-two HIV-1 seropositive patients was used.  Baseline CD4 counts were between 200H10⁶/L and 500H10⁶/L and viral loads were all less than 10,000 RNA copies/mL.  Thirty-nine subjects received IL-2 injection and ART, while 43 received ART alone.  After one year of following this treatment regimen, patients who received IL-2 and ART had an increase in CD4 count of 112%.  Patients using ART alone saw an 18% increase in CD4 cells.  A decrease in viremia accompanied the increase in CD4 counts.  Twenty of thirty patients receiving IL-2 showed final viral loads of less than 50 RNA copies/mL as compared with thirteen of thirty-six patients using ART alone.  It is notable, however, that certain toxic effects were noted due to IL-2 usage.  Common adverse effects were fever, fatigue, and myalgia.  More serious effects were observed in approximately 50% of the patients receiving IL-2.  Three very serious side effects (thrombophlebitis, increased bilirubin, and acute exacerbation of mania) occurred individually in three subjects.  One patient developed hyperthyroidism secondary to the IL-2 and now requires hormone supplementation after becoming hypothyroid after treatment (34).

The human body has two branches of its immune system: cell-mediated immunity (CMI) and antibody-mediated immunity (AMI).  In order to control infection, the host must be able to use both arms of defense.  Accordingly, researchers have vaccines in development that stimulate production of HIV-1 specific antibodies, viral destruction by specific immune cells such as cytotoxic T lymphocytes, or both.

The earliest and most prevalent research has been devoted to production of a vaccine that produces antibodies to viral epitopes.  As noted previously, the two main antigens on the surface of HIV-1 are the gp120 and gp160 proteins.  Researchers have been attempting to use these surface molecules to induce an immune response that will produce deactivating antibodies to the virus.  The first generation of these vaccines achieved the induction of neutralizing antibodies in nearly all of the subjects tested (5).  However, the antibodies produced by the vaccinees were mainly directed against homologous laboratory strains of the virus and showed little if any cross reaction with actual wild type viral strains.  This inability to neutralize wild viruses has been interpreted as a general failure of this method.  A double-blind study done recently illustrates the inefficiency of a gp160 or gp120 vaccine.  The trial tested 835 seropositive patients with CD4 counts >200H10⁶/L.  Half of the group received 160Fg of gp160 every three months for three years duration and the other half received a placebo on the same time scale.  The researchers found that despite vaccination, the time to clinical endpoint (AIDS defining event or death) did not differ between the two groups.  A higher proportion of the vaccinees did have higher than baseline CD4 counts at six months, but the overall interpretation of the results was that immunization with gp160 has only a modest effect on CD4 cell counts and this treatment alone was of no clinical benefit (35).  Despite the marks against this type vaccine, there are many in phase II and III of clinical trials both in the United States and Thailand.  Their actual efficacy needless to say has been limited (5).

Realizing that immunization with whole gp120 protein is ineffective, researchers began looking for specific segments of the protein that may be highly conserved between variants of the virus.  A certain section of the gp120 protein called the V3 loop is thought to form part of the co-receptor binding site.  Scientists theorized that this section of protein would be relatively homologous between strains because it performs a very important viral function: assistance in penetration of the host cell.  This V3 loop is a very good target for neutralizing antibodies, but it had been shown that laboratory strain produced antibodies show little cross reaction between virus types.  One method of circumventing this problem is to use antigens from primary isolates (wild types) of the virus.  A study done recently shows that V3 loops from six different primary isolates when conjugated to purified protein derivative (PPD) of M. tuberculosis can induce a broad antibody response that is effective against many heterologous strains of virus (10).  The trial was conducted using seven HIV-1 seropositive and PPD skin test positive subjects.  Intradermal injections of the multi-epitopic V3-PPD conjugate were given monthly for the initial three months and then every three months thereafter to eighteen months.  To show correlation, two groups of guinea pigs were also given injections.  The control guinea pigs received monovalent vaccine developed from HIV-1_MN, and the experimental animals received the same vaccine as did the human subjects.  The results showed that the guinea pigs vaccinated with the monovalent conjugate showed antibody neutralization of HIV-1_MN, but were inactive against other strains of HIV-1.  On the other hand, antibodies from both guinea pigs and humans were sufficiently cross-reactive as to neutralize primary isolates of HIV-1 whose V3 loop structure differed greatly from the ones contained in the multi-epitopic vaccine.  The effect on blood viral load was also significant.  Four of the seven patients had baseline viral loads of <400 RNA copies/mL.  The remaining three had baseline loads between 8000 and 12,000 RNA copies/mL.  All three of these patients experienced a decrease in viral load.  Serum virus concentration in two of the three subjects dropped twofold to <400 copies/mL, and viremia in the third subject decreased fivefold.  However, six to twelve months after vaccination, when antibody concentrations declined, plasma viral loads increased to between 10,000 and 70,000 RNA copies/mL in six of seven patients (10).

V3 loop conjugate immunizations like these seem to have some advantages over gp120 and gp160 vaccines.  V3 loop vaccines induce a higher concentration of neutralizing antibodies than the gp120 and gp160 types.  They also induce a small amount of CD4 and CD8 cytotoxic T lymphocytes.  Very important too was that the V3 loop vaccines caused secretory IgA immunoglobulins to be produced (10).  Given the methods of HIV-1 transmission, mucosal surface protection by secretory IgA would seem to be very advantageous.

Perhaps due to researchers= frustrations about gp120 and gp160 derived vaccine failures, more recent studies have investigated ways to stimulate cytotoxic T lymphocytes (part of cell-mediated immunity) to fight the virus.  One type of vaccine that can do this relatively effectively is a DNA vaccine.  A study published recently in Science magazine (36) indicates that although a purely cell-mediated immune response to the virus will not prevent infection, it may be able to alter the disease course significantly enough so that viral infection will not necessarily lead to clinical symptoms.  Barouch et al. formulated a vaccine that consisted of the env gene from HIV-1 and the gag gene from Simian Immunodeficiency Virus (SIV).  This mixture, along with a solution of human IL-2, was injected into an experimental group of Rhesus monkeys while a control group of otherwise identical monkeys received a placebo vaccine.  When challenged with live virus, both groups of animals were not protected from infection, but the disease course observed varied remarkably between the two groups.  The placebo vaccinated animals showed only a weak immune response and half of them died within 140 days of initial viral exposure.  Conversely, the monkeys immunized with the functional DNA vaccine showed lowered primary viremia and quickly developed a strong cytotoxic T cell proliferative response.  As a consequence, these animals were able to control viral replication and maintained stable CD4 T cell counts (36).  It is important to note that these findings may or may not correlate in human subjects.  More research is needed in this area to determine whether the vaccine=s effects in monkeys are generalizable into the human population.

Most scientists now believe that in order to protect individuals from infection by HIV-1, elicitation of not one but both arms of the immune system is needed.  One of the reasons they think this is that the cytokine profiles (levels of IL-2, IL-10, interferon etc.) seen in HIV-1 negative subjects injected with HIV-1 antigens indicate that both sides of immunity are working simultaneously to clear the host of the foreign virus particles.  In their plasma, one is able to detect interferon gamma (IFN-γ) which aids in cell-mediated immunity and also IL-10 which aids in antibody-mediated immunity (37).

In response to this idea, researchers have begun looking at methods of immunization that do indeed stimulate the entire immune system.  The main type currently under study is called the prime-boost vaccine.  In this method, the host is initially injected with a recombinant virus (usually a type of canarypox) that expresses multiple types of HIV-1 envelope proteins.  This virion will typically elicit a cell-mediated cytotoxic response.  After priming the immune system to produce HIV-1 specific cytotoxic T cells, the subject is then given a booster shot of pure gp120 protein from one or more viral strains.  As discussed above, gp120 primarily elicits an antibody response.  Early results from testing this type of vaccine showed activation of cross reactive cytotoxic cells but little production of cross reactive neutralizing antibodies.  However, recent studies have found that this type of prime-boost vaccine may be more reactive than previously believed (38).

One such study indicates that the antibodies produced by this vaccine type are not necessarily specific only for the species of HIV-1 that stimulated their production, but they can be specific for multiple strains, called clades, of the virus (most research done in the United States uses HIV-1 viruses that are of clade B).  In this most recent research, sera from twenty vaccinated volunteers was tested for cross reactivity with V3 peptides from clades A, B, C, D, E, F, G, H, and O.  The vaccine used consisted of a recombinant canarypox vector expressing gp120_MN, gp41_LAI, and viral products produced from the gag and pol genes for the prime, and gp120_SF2 for the boost.  Following a standard immunization regimen, the subjects were bled and their sera tested.  Amazingly, all serum samples exhibited at least some cross reactivity.  All sera was reactive with most of the V3 peptides from clades B, C, and F.  More moderate reactivity was noted to clades A, D, G, and H.  No cross reactivity was seen for the V3 loop from clades E or O (38).  While these results seem promising, one should keep in mind that the antibody reactivity seen in this data cannot be construed as broad enough to impart immunity, and whether this vaccine regimen would give at least some real protection from HIV-1 infection cannot be judged without significantly more research and actual clinical trials.

Another method to stimulate the entire immune system is by presentation of a whole killed or otherwise deactivated virus.  This is how the first vaccines ever developed were made, so it seems logical that an HIV-1 vaccine that uses a whole virus would be very effective.  However, injection of the virion into an otherwise healthy individual is not currently advisable as it may cause disease.  This fact has been a major stumbling block for research into vaccines of this type.  Still, studies have been completed using a deactivated HIV-1 immunogen (Remune) injected into seropositive patients.  The Remune vaccine is an inactivated, gp120 depleted virion.  The idea of one study was to see if concomitant usage of Remune and traditional antiretroviral therapies would induce a strong immune response to many different types of HIV-1 virus.

Current drug therapies do lower viral load considerably, but have little effect on immune system reconstitution.  Prior to immunization with Remune, subjects only mount a scanty lymphoproliferative response to viral antigens.  This, of course, is due to viral suppression of the immune system.  Researchers hypothesized that an inactivated virus vaccine could possibly stimulate the immune system into renewed production of T helper and T cytotoxic cells.  The aforementioned study used eleven seropositive, antiretroviral drug using patients who received intramuscular injections of Remune and p24 antigen once a week for twelve weeks (39).  After immunization, the subjects= sera were analyzed and found to have strong cell-mediated and antibody-mediated immune responses to whole HIV-1 antigens of multiple types (39).  This cross reaction is possibly due to presentation of the viral antigens in their native form.  This vaccination method may work relatively effectively but until the ethical issues of injecting whole virus into uninfected patients is resolved, no late stage research or clinical efficacy trials will ever be conducted. 

In addition to prime-boost and whole inactivated virus immunization strategies, immunologists have been experimenting with more novel vaccine types.  One of these methods uses recombinant strains of Herpes Simplex Virus (HSV) to impart immunity to SIV in rhesus monkeys.  One of the principal problems with many current vaccine types is that they do not induce a long-lived immune response.  This is due to rapid degradation of HIV-1 antigens or canarypox vectors by the body.  HSV on the other hand can persist for the lifetime of the infected host in a latent stage and can periodically reactivate (40).  A group of seven rhesus monkeys were immunized with either replication-competent or replication-deficient recombinant HSV capable of expressing SIV env and nef proteins.  One control monkey was injected with normal replication-competent HSV.  In all experimental animals a strong initial antibody response was noted.  A strong cytotoxic response was noted at four weeks following first injection.  Challenge with SIV was done at twenty-two weeks after the last booster.  This time frame represented between thirty-two and sixty-two weeks from the beginning of the injection series.  All control monkeys became infected with the virus and one died at ten weeks.  Two of the seven experimental animals were completely protected from infection (39).  Twenty-nine percent protection may not sound so good, but bear in mind that challenge was performed at up to sixty-two weeks following initial vaccination.  Most studies challenge at four weeks when the immune response is at its peak (39).  Also, this is one of the first studies done that showed complete protection without eventual detrimental side effects.  The strain of SIV used in this study was a particularly nasty one and to see such protection is remarkable.  Preliminary research using more advanced HSV vectors is even more promising.  Perhaps with improved vector designs, researchers may be able to begin study in humans to ascertain whether this vaccine type is efficacious in subjects besides rhesus monkeys.

This section of the paper has looked at a number of different vaccine types currently under study.  The HIV-1 virus infects the host=s immune cells and creates a state of suppressed immune responsiveness.  It can actively replicate and kill the cells, remain latent inside them, or produce a state of anergy in them.  It is a highly mutable virus.  Researchers have experimented with methods to recover immune function in patients with AIDS.  Many unique and somewhat clever vaccine types are currently being researched.  These methods range from the gp120 and V3 loop vaccines that stimulate humoral immunity, to DNA vaccines that do not prevent infection but alter the clinical course of disease, to prime-boost vaccines that elicit both a humoral and cell-mediated immune response.  Scientists are also beginning to investigate how injection with inactivated virus might help reconstitute the immune response in HIV-1 positive patients and how they may be able to use this type of immunization as a preventive vaccine.  The most recent studies discussed in this paper experiment with more novel HIV-1 antigen vectors such as recombinant HSV and what type of immune response they elicit.  This area shows some of the more promising results as at least some of the study subjects were protected from viral infection.  However, most of the research studies and clinical trials underway at this time do not impart a sense that this road to finding an HIV-1 vaccine is nearing its end.

Having looked at both the chemical and microbiological methods to treat HIV/AIDS, this paper shall now delve into the psychological aspects of treatment.  This area is in many ways more difficult to discuss than the others.  There is still a dearth of information available as it relates to the psychological treatment of AIDS patients.  Not much research has been done to realize the specific methods by which therapists should conduct their sessions.  The assumption perhaps exists, that one should treat all mental health issues identically regardless of their cause.  Irrespective of the relative lack of information available, this paper will introduce the subjects of epidemiology, behavioral challenges in medication adherence, psychotherapy, psychiatric care, support groups, and self motivated coping.  After introduction of these methods, the issue of dying well will be briefly discussed.

The mental health care of terminally ill patients is an extremely difficult area and the treatment of HIV infected individuals is no different.  Further compounding the issue is that AIDS patients are no longer found just in the subgroup of homosexual men.  The epidemiology suggests that 0.3% of all individuals in the United States are HIV positive.  Gay men still account for 35% of newly reported cases, but between 5% and 60% (dependent upon location) of IV drug users, 0%-57% of prostitutes, 0.5%-11% of STD clinic patients, 4%-19.4% of seriously mentally ill patients (41), and 0.15% of women are HIV positive (16).  It is remarkable that in 1998, women accounted for 23% of new AIDS cases compared to 7% in 1985 (16).  As one can see, the demographic of HIV infected individuals is rapidly changing and psychotherapy methods must evolve to match the clientele.

As one can imagine, psychological stress from HIV infection comes from many areas.  One of these is the significant problem of drug toxicity.  The medications involved in AIDS treatment can cause side effects such as: nausea, diarrhea, pancreatitis, lactic acidemia, redistribution of body fat, diabetes, and death just to name a few (16,42).  Dealing with these problems can be a monumental task and some individual cope by not taking their medications.  Studies show that 40%-60% of patients are <90% adherent (43).  This is a behavioral problem best dealt with by standard behavior modification techniques.  The first thing to realize is that, in any behavior modification scenario, the individual must initially be educated and motivated (43,44).  The therapist can help them define the behavior they wish to accomplish.  The patient must know the objective of the treatment plan and the direct effects of nonadherence.  Information about medications should be provided consistent with the patient’s literary level.  This information should include explanations of possible side effects.  This is the education patients must have if they are to be effective in their treatment.  They must also be motivated by appropriate goal setting paired with timely feedback to give either reward (lower viral load) or punishment (increased viral load).  In addition to goal setting, other methods of motivation should be used.  The therapist can work directly with the prescribing physician to simplify the drug regimen and, if possible, tailor treatment to the patient’s lifestyle (45). When the initial steps have been completed and the patient is compliant, the therapist must then be prepared to address any concrete issues that arise.  Life situations such as lack of adequate transportation to medical appointments or lack of funds to pay for them are issues outside the realm of actual treatment that need to be dealt with.  Also because depression and substance abuse (common comorbidities with AIDS) can reduce adherence, these disorders should be recognized and treated (43).  HIV/AIDS is a complex disease that requires complex treatment.  However, adherence to the treatment regimens can indeed bring about an increase in overall health and thus lead to a decrease in mental health care issues such as depression and suicidal ideation.

The stress and anxiety associated with HIV positive serostatus comes from many levels: learning of status, deciding who to tell about it, fear of abandonment, loss of control, coping with the healthcare system, side effects of treatment, and the expense of treatment (13).  The major form of psychological distress comes from preoccupation with illness and the potential for a rapidly declining path to death (46).  Patients can deal with some of these issues by attending and participating in sessions of psychotherapy.  The initial step of therapeutic intervention should be a basic assessment of the individual.  In this setting, the practitioner will examine the patient’s coping abilities, support network, resource systems, level of understanding of HIV/AIDS, and basic financial, emotional, employment, and adjustment needs (47).  Behaviors that affect the patient’s health and medical treatment should also be noted.  These would include intravenous or other drug use, unprotected sex, and non-adherence to medical regimens.  Special attention should be given to suicide risk (47).  The assessment should also include a discussion of where the patient wants to go with his or her treatment.  This initial assessment will provide the therapist with the required knowledge to provide direct interventions.

To provide the necessary interventions, such as grief counseling and guilt resolution, the therapist must be able to relate to and deal with emotions of anxiety, depression, feelings of isolation, anger, intense fear, embarrassment, and denial.  An important factor in the care of the AIDS patients is the attitude and response of caregivers (46).  The therapist should be aware of his or her own possible negative attitudes towards HIV infection, fears of contracting the disease in the course of therapy, homophobia, and other prejudices.  In order to give accurate responses to questions by patients, practitioners should keep themselves up to date on newly emerging information.  In addition, patients should be allowed to express the anger they may feel.  Research has shown that if negative emotions are directed toward something constructive, positive outcomes result (46).

It may be found that some patients do not respond well to therapy in the attempt to alleviate the symptoms of depression and anxiety.  Additionally, in some instances, the HIV virus will cross the blood brain barrier and attack the dendritic cells of the central nervous system.  The loss of these and other brain cells result in a series of symptoms such as deep lethargy, manic-depressiveness, and psychosis.  Collectively this syndrome is known as AIDS dementia complex (ADC) (48).  The patient afflicted with ADC or the one who does not improve with psychotherapy alone should seek help from a psychiatrist who can prescribe psychotropic medications to alleviate the patient’s symptoms.  The treatments for the above listed disorders are varied and this section will discuss them in turn.

Rates of depression are higher in patients infected with HIV than in patients with other medical conditions.  As many as 33% of HIV positive individuals suffer from major depression (49).  According to the Diagnostic and Statistical Manual fourth edition (DSM-IV), diagnosis of depression requires the presence of at least five symptoms such as depressed mood, loss of pleasure, insomnia, fatigue, worthlessness, diminished interest, agitation, and decreased libido.  These should be present most of the day and should represent a change from previous functioning (50).  In addition to psychotherapy, there are a few medical methods to treat the symptoms of depression.  Two types of antidepressants exist that can be used in the AIDS patient: tricyclics and serotonin-specific reuptake inhibitors (SSRIs).  The tricyclics such as Elavil and Sinequan are sedating and should be used with caution as overdose can cause death.  They also have significant side effects.  They can be exploited to the patient’s benefit however.  Doxepin is a sedative and can cause constipation.  This drug can be optimally used in the patient who is agitated and has problems with diarrhea secondary to antiretroviral therapy.  The effect is to decrease agitation and reduce the severity of diarrhea.  As a caution, tricyclic antidepressants should not be used concomitantly with PIs (51).  If tricyclics are contraindicated, SSRIs should be used.  They are newer and have fewer side effects.  Drugs such as Prozac should be started with a low dose and slowly increased to therapeutic levels.  If the drug does not work adequately, discontinue the medication slowly and allow some time for it to be completely eliminated before starting a new drug (51).  In the patient with anxiety, SSRIs are sometimes indicated in that the anxiety can be depression related.  If anxiousness exists separately, benzodiazepines with short half lives or non-benzodiazepine drugs such as BuSpar are recommended.  As is the case with tricyclics, the concomitant administration of benzodiazepines and PIs is contraindicated (they are both metabolized by cytochrome P-450) (51).

ADC is a chronic and debilitating encephalitis with a distinct clinical syndrome characterized by a downward trend in cognitive, behavioral, and motor abilities.  Psychosis may also be a part of the clinical presentation (52).  The prevalence of psychosis in late-stage AIDS patients is 0.1%-5% (53).  The psychotic patient has trouble functioning because of severe emotional and cognitive difficulties.  The presence of hallucinations, delusions, and bizarre behavior and speech are common (54).  In these cases, the standard anti-psychotics such as Risperdal and Ativan should be used cautiously.  Perhaps a better solution should be to use a mid-range antipsychotic such as Haldol.  Drugs such as this have been shown to be effective and have fewer side effects (51).

The psychological interventions discussed thus far all require the involvement of a highly trained (read: expensive) practitioner.  The following section will discuss the methods of psychological treatment used by those individuals who prefer to be more involved in helping themselves and others.  These include support groups (and how they have changed as a result of longer survival) and self-motivated coping.

AIDS has always been more of a socioeconomic minority disease.  Therefore, individuals infected with HIV have used support groups and forums widely for emotional support and for political voice.  Through the utilization of support groups, individuals feel emotional closeness and support in their fears, losses, and victories.  Historically, the focus of discussion has been centered on the intense fear of debilitation, loss of control, and sudden death.  However, the advent of PIs and the initiation of combination therapy has been successful in lowering viral loads, increasing CD4 cell counts, and improving the overall health of HIV positive individuals.  Because of this, there has been a shift in the concerns of AIDS support group participants.  The focus now exists on whether members have had success with their treatment regimens, had many or no side effects, or whether individuals have opted out of treatment due to concerns about excessive toxicity (55).  For those individuals who have had decreased viral loads secondary to antiretroviral therapy, fears of impending death have been replaced by insecurities about a future that was not previously considered possible.  A survey conducted by the Gay Men’s Health Crisis in 1996 found that in the population of individuals benefiting from antiretroviral therapy, financial security was the biggest concern (56).  In the day of failing therapies it was not unusual for individuals to spend their life savings to live well in anticipation of a short life ahead.  Now that there is a foreseeable future, it is regarded with cautious optimism in the face of an extremely limited income.  The possibility a sudden failure of the medication is also a source of stress.  The now healthy AIDS patient struggles with issues of family planning, relational arrangements, long-term effects of medications, and lack of adequate knowledge and foresight to make these necessary decisions.

Most AIDS patients benefit from therapy, but some individuals, for as yet unknown reasons, do not see a decrease in viral load or an increase in CD4 cell concentration.  These individuals represent approximately 20% of the population on such therapies (16).  They make up a small yet important minority in the support group subculture.  They often feel they have lost touch with the rest of the population of people living with AIDS.  Therefore, as a reactionary measure, such individuals have begun support groups of their own to discuss their unique concerns.  However, recruitment efforts have been ineffective probably because of reluctance to be identified with this new population (55).

Naturally, all of these support groups have a leader of some kind.  This person is usually a volunteer social worker or clinical psychologist.  With the discussion in the groups becoming less crisis driven and more oriented toward a focus on life planning, the leader may feel less useful than in the past.  Therefore, the leader must change his or her methods to help facilitate discussion of these new and hopeful subjects (57).  With the changing dynamic it is common for group participants who are enjoying success to minimize their hopefulness in an attempt to protect those members who have had less success with their medications.  The tendency for the group to protect itself in this way can lead to decreased feelings of safety and affiliation (55).  The group leader must be sensitive to this and encourage complete honesty from the individuals participating in the discussion.  The leader must also be aware of the defense mechanisms used by AIDS patients and assist them to correct possible thinking errors.  Issues of hopefulness must be encouraged and combined with experiences of anger, confusion, and despair which invariably occur in the support group participants (57).  Thereby the leader will help foster an attitude of honesty and build a relationship of trust with the members and thus facilitate positive outcomes.

While the AIDS patient has much support when participating in psychotherapy or support groups, the individual must have a reserve of coping skills to support themselves in the absence of peers.  A recent study was done that discovered three main themes by which HIV positive individuals overcome the suffering they face: creating a meaningful life pattern, connectedness, and self-care (58).  Interviews were done with several HIV positive individuals with diverse backgrounds.  Afterward, a coding process was done to assign different thoughts and statements into categories.  Thus the three main themes emerged from the data provided by the participants.  The small sample size could be thought of as a limiting factor in this data interpretation, but numerous studies have found that individuals who transcend above their pain and suffering do so in a manner consistent with these three themes (59).  In addition to these methods of coping, research has found that most individuals “manage” and “tolerate” rather than “master” and “eliminate” the psychological difficulties that result from HIV positive serostatus.  This involves different coping strategies at different stages of disease.  For instance, in studies of asymptomatic HIV positive individuals have shown that avoidant coping (harness the good, block out the bad) do not protect them from distress.  Conversely, this coping method is quite effective in patients will full blown AIDS (41).  Other research suggests that gaining a sense of control over events and effecting positive change in life seems to promote psychological well-being (41).

Although antiretroviral therapy is quite effective at increasing physiological health and therapy, psychotropic medications, support groups, and coping skills are effective at improving mental health, AIDS is still very much a terminal illness.  Regardless of the tenacity of the individual, one day they will die from HIV infection.  It is often difficult for all parties involved to determine when the patient has made the jump from living with the disease to dying from it.  The five Kübler-Ross stages of death and dying (denial, anger, bargaining, depression, and acceptance) (60) seem to be universal and AIDS patients go through them as well.  The psychotherapist must understand this and be prepared to initiate discussion on this somber topic.  A useful method for doing this is to ask the person what they believe happens after death and whether or not they find those beliefs comforting (61).  Since few therapists have received specific training on counseling individuals who are at the end of their lives, much of the discussion will be improvisational.  The clinician’s own feelings about death will undoubtedly have an effect on the work he or she does with patients who are at the end of their lives.  There are some recommendations for topics to discuss toward the end of the patients life.  One article states seven crucial points to talk about:  which hospital to use in case of an emergency, who is their main contact person, make a list of all medications and dosages to be brought to the hospital in case of emergency, discuss advance medical directives (life saving heroics etc.), prepare a living will, designate a health care proxy, and make a decision on a “do not resuscitate” order (61).  The therapist should also help the individual make arrangements for a memorial service.

Patients should be informed that they have choices available to them on how they would like to go about the business of dying.  Questions such as: where would the patient like to die, whom would they like to be at their side, would they like last rites or other religious visits, and is there anything they haven’t said to their loved ones should be answered.  The patient should be aware of pain management options available to him or her.  Most people believe that they will be in agonizing pain when they die.  This need not be so.  Their physician can order a morphine drip to eliminate pain but maintain alertness.  Before the morphine starts, the therapist should facilitate interaction between the patient and his or her loved ones.  This is a stressful time for everyone and the therapist is wise to make suggestions for discussion such as: is there anything that the patient hasn’t said, say I love you and thank the patient for all the wonderful times spent together, and, lastly, say good-bye and express how much the dying individual will be missed, but maintain the assurance that everything will be alright (62).  The care of the dying individual is extraordinarily stressful.  However, as Shernoff has pointed out, “By confronting with dying clients the fragility of life and the value of each day, health care professionals begin to confront the vulnerability of their own lives and to acquire a deeper appreciation of living.”

This paper has looked at HIV/AIDS and some various components of its treatment.  It began with a discussion of the virus itself, its biochemistry and genetics, and some immune aspects of infection.  It then continued into the chemical aspect of treatment by introducing existing antiretroviral medications and some interesting projects under study.  Then some vaccine types being developed were examined.  Following this some of the psychology surrounding the disease was discussed.  With all this in mind, one may see that the current state of HIV/AIDS therapy is much better now than it ever has been.  However, one must realize that there is an outstanding amount of information that is still unknown and that there is therefore still a long road ahead.

Works Cited