Immune Reconstitution and other Approaches

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.