We are just beginning to learn about the immune reconstitution attained when HIV-infected patients attain substantial viral suppression with highly active antiretroviral therapy. For the first few months of therapy, patients have a relatively rapid increase in their CD4+ cell population that can be to a large extent explained by an expansion of their pre-existing memory CD4 cells. However, such patients have also been observed to have a gradual increase in their naive (CD45RA+) CD4+ T-cell population.

This can occur even in patients who begin with very low CD4 counts. This finding raises the possibility that such patients may be able to at least partially reconstitute their immune system, have an increase in the number of naive T cells, and recover some of their T-cell immune defect. At the same time, physicians should realize that such patients still can retain substantial gaps in their immune repertoire. In particular, they can still develop opportunistic infections even when their CD4 counts have risen to levels that are infrequently associated with such infections. However, there is some evidence to suggest that partial reconstitution of the immune repertoire and ability to defend against such infections can occur and this will be an important area for research in the next several years.

The demonstration that HIV replication can be effectively suppressed with antiretroviral therapy has also renewed interest in more direct approaches to immune reconstitution. Even before the development of highly active three-drug regimens, it was shown that intermittent administration of interleukin-2 could induce an increase in the peripheral CD4 count in HIV-infected patients who began with over 200 CD4 cells/mm³ . A theoretical concern of this approach is that interleukin-2 can stimulate HIV replication. However, this effect appears to be minor and with the present highly active regimens can be easily controlled. It remains to be shown whether this increase in CD4 cells is accompanied by a functional improvement in the immune system, and a large-scale international trial is in progress to assess this point.

A variety of other approaches for immunoreconstitution in HIV infection are either under consideration or actively in clinical trial, including interleukin-12, a combination of interleukin-2 and interleukin-12, and interleukin-15. Also, there is some renewed interest in boosting the specific immune response to HIV through therapeutic vaccination. Ultimately, the aim of all such approaches is to achieve a reconstituted immune system that can also suppress the replication of HIV. Even if complete eradication of the virus is not possible, long-term control of HIV may be feasible and permit a prolonged survival.

At the same time, the available approved drugs permit only a limited number of three-drug regimens to be sequentially used in a given patient, and there remains an urgent need for new effective therapies. We have discussed some of the NRTIs, the NNRTIs, and the PIs under development. There also continues to be a substantial interest in developing drugs that act at new viral targets. Such agents, used in combination with the presently available drugs, may enable even more complete and sustained viral suppression to be attained. It was known for some time that one cellular receptor for HIV was CD4. It has recently been shown that certain chemokine receptors act as a co-receptor for HIV.

The most important of these are CCR5 for monocytotropic strains and CXCR4 for T-tropic strains. Moreover, individuals with a homozygous deletion in the CCR5 receptor have been shown to be naturally resistant to becoming infected with HIV. Agents that block the binding of HIV to these receptors have been identified, and one such agent, T-20, has been shown to have clinical activity in early trials. It is possible that other strategies including gene therapy might also be able to take advantage of this finding.

Another target of interest is HIV integrase, which catalyzes the insertion of the HIV provirus into the target cell DNA. There is an effort underway to identify specific inhibitors for this enzyme. Another novel target is the HIV-1 nucleocapsid protein zinc fingers. These are structural components necessary for both acute infection and virion assembly. Their protein sequence is very highly conserved, and it has been hypothesized that they might be relatively resistant to mutation. Several inhibitors have been identified, and at least two are now in clinical trial.

Substantial advances have been made in AIDS therapy over the past several years. The development of highly active combination regimens of NRTIs and PIs has represented a substantial advance. Patients on these regimens have had substantial increases in their CD4 counts, fewer opportunistic infections, and prolonged survival. These advances have also resulted in a substantial drop in the death rate from AIDS starting in about 1996. In addition, the widespread use of zidovudine in the peripartum period has resulted in a marked drop in the incidence of vertically acquired HIV infection.

At the same time, the available regimens are quite expensive and require taking many pills daily in a complex schedule. This is an impediment for patient compliance. There is a need for simpler effective drug regimens, ideally involving once-daily dosing. We do not know how long the viral suppression attained with potent three-drug therapies will last when these regimens are used as initial therapy. Also, as we have seen, once patients fail their initial regimen, further therapeutic regimens are generally not as effective. Complete eradication of HIV remains an elusive goal, because memory T cells can serve as a long-lived reservoir for HIV, and it is quite possible that other reservoir sites (such as the brain) will be identified. For these reasons, it is important that we not get lulled into a false sense of security but rather use this period to redouble our efforts to develop long-lasting effective therapies for this disorder.

References:

_{Carpenter CCJ, Fischl MA, Hammer SM, et al: Antiretroviral therapy for HIV infection in 1997: Updated recommendations of the International AIDS Society-USA Panel. JAMA 277:1962-1969, 1997. Describes one recent set of therapeutic recommendations.}

De Clercq E: Toward improved anti-HIV chemotherapy: Therapeutic strategies for intervention with HIV infections. J Med Chem 38:2491-2517, 1995. Review of the medicinal chemistry of anti-HIV drugs.

Deeks SG, Smith M, Holodniy M, Kahn JO: HIV-1 protease inhibitors: A review for clinicians. JAMA 277:145-153, 1997. Clinical overview of HIV protease inhibitors.

Delta Coordinating Committee: DELTA: A randomized double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine monotherapy in individuals with HIV infection. Lancet 348:293-291, 1996. A second trial examining combination NRTI therapy.

Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. November 5, 1997. http://www.cdcac.org or http://www.hivatis.org>. Provides guidelines for HIV therapy.

Eron JJ, Benoit SL, Jemsek J, et al: Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N Engl J Med 333:1662-1669, 1996. Results of a clinical trial utilizing zidovudine and lamivudine.

Flexner C: HIV-protease inhibitors. N Engl J Med 338:1281-1292, 1998. General review of protease inhibitors.

Hammer S, Katzenstein D, Hughes M, et al: A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 335:1081-1090, 1996. Results of a clinical trial showing the superiority of combination therapy over zidovudine monotherapy.

Hammer SM, Squires KE, Hughes MD, et al: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 337:725-733, 1997. Results of a clinical trial showing the superiority of three-drug combination therapy involving a protease inhibitor over two-NRTI therapy.

Roberts NA, Craig JC, Sheldon J: Resistance and cross-resistance with saquinavir and other HIV protease inhibitors: Theory and practice. AIDS 12:453-460, 1998. Article describing patterns of PI resistance and how they can influence therapeutic decisions.