Treatment and Prevention of AIDS and Vaccine Development

Vaccination Is Not Immunization Vaccine Risks Exposed

Vaccines Have Serious Side Effects

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Active research efforts have been aimed at developing reagents that interfere with the viral life cycle. Treatment of HIV infection and AIDS now includes the administration of three classes of antiviral drugs, used in combination, that target viral molecules for which no human homologues exist. The first antiretroviral drugs to be widely used were nucleoside analogues that inhibit reverse transcriptase activity. These drugs include deoxythymidine nucleoside analogues such as 3'-azido-3'-deoxythymidine (AZT), deoxycytidine nucleoside analogues, and deoxyadenosine analogues. When these drugs are used alone, they are often effective in significantly reducing plasma HIV RNA levels for several months to years, but they usually do not halt progression of HIV-induced disease, largely because of the evolution of virus with mutated forms of reverse transcriptase that are resistant to the drugs. Non-nucleoside reverse transcriptase inhibitors directly bind to the enzyme and inhibit its function. Viral protease inhibitors have been developed that block the processing of precursor proteins into mature viral capsid and core proteins. When these protease inhibitors are used alone, mutant viruses resistant to their effects rapidly emerge. However, protease inhibitors are now being used in combination with two different reverse transcriptase inhibitors. This new triple-drug therapy, commonly referred to as HAART (highly active antiretroviral therapy) or ART (antiretroviral therapy), has proved to be effective in reducing plasma viral RNA to undetectable levels in most treated patients for up to 3 years. An integrase inhibitor is also now used as part of antiviral therapy. "Entry inhibitors," which prevent viral entry by targeting either CD4 or CCR5 on the host cell or gp41 or gp120 on the virus, are another novel category of therapeutics. Maraviroc is an entry inhibitor that blocks CCR5 and thus prevents viral entry. Drugs that target gp41 include compounds such as enfuvirtide that prevent fusion of the viral envelope with the host cell plasma membrane. Although antiretroviral therapy has reduced viral titers to below detection for up to 10 years in some patients, it is unlikely that such treatment can eliminate the virus from all reservoirs (especially long-lived infected cells), and resistance to the drugs may ultimately develop. Other formidable problems associated with these new drug therapies, which will impair their effective use in many parts of the world, include high expense, complicated administration schedules, and significant adverse effects.

The individual infections experienced by patients with AIDS are treated with the appropriate prophylaxis, antibiotics, and supportive measures. More aggressive antibiotic therapy is often required than for similar infections in less compromised hosts.

Efforts at prevention of HIV infection are extremely important and potentially effective in controlling the HIV epidemic. In the United States, the routine screening of blood products for evidence of donor HIV infection has already reduced the risk of this mode of transmission to negligible levels. Various public health measures to increase condom use and to reduce the use of contaminated needles by intravenous drug users are now widespread. Perhaps the most effective efforts at prevention are campaigns to increase public awareness of HIV.

The development of an effective vaccine against HIV is a priority for biomedical research institutions worldwide. The task has been complicated by the ability of the virus to mutate and vary many of its immunogenic antigens. It is likely that an effective vaccine will have to stimulate both humoral and cell-mediated responses to viral antigens that are critical for the viral life cycle. To achieve this goal, several approaches are being tried for HIV vaccine development. Much of the preliminary work has involved simian immunodeficiency virus (SIV) infection of macaques, and effective vaccines against SIV have already been developed. This success is encouraging because SIV is molecularly closely related to HIV and causes a disease in macaques that is similar to AIDS in humans. Various live virus vaccines have been tested in the hope that they will induce strong CTL responses. Such vaccines include nonvirulent recombinant hybrid viruses composed of part SIV and part HIV sequences or viruses that have been attenuated by deletions in one or more parts of the viral genome, such as the nef gene. One concern with live virus vaccines is their potential to cause disease if they are not completely attenuated and possibly to recombine with wild-type HIV to produce a pathogenic variant. Another approach that avoids this safety concern but retains efficacy in inducing CTL-mediated immunity is the use of live recombinant non-HIV viral vectors carrying HIV genes. Preliminary trials in human volunteers have already shown that canarypox vaccines expressing several HIV-1 genes can induce strong CTL responses to the HIV antigens. Many DNA vaccines have also been studied; these vaccines are composed of combinations of structural and regulatory genes of SIV or HIV packaged in mammalian DNA expression vectors. Combinations of vaccines, such as initial immunization with a DNA vaccine followed by boosting with a canarypox vector expressing HIV genes, have yielded some of the most promising results to date. Recombinant protein or peptide subunit vaccines that elicit antibodies have so far been of limited value because the antibodies induced by these vaccines typically do not neutralize clinical isolates of HIV. Attempts are currently under way to generate vaccines that can induce neutralizing antibodies to HIV.

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