Developing strategies for HIV-1 eradication

Abstract

Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication, transforming the outlook for infected patients. However, reservoirs of replication-competent forms of the virus persist during HAART, and when treatment is stopped, high rates of HIV-1 replication return. Recent insights into HIV-1 latency, as well as a report that HIV-1 infection was eradicated in one individual, have renewed interest in finding a cure for HIV-1 infection. Strategies for HIV-1 eradication include gene therapy and hematopoietic stem cell transplantation, stimulating host immunity to control HIV-1 replication, and targeting latent HIV-1 in resting memory CD4(+) T cells. Future efforts should aim to provide better understanding of how to reconstitute the CD4(+) T cell compartment with genetically engineered cells, exert immune control over HIV-1 replication, and identify and eliminate all viral reservoirs.

Figure 1

Dynamics of viral replication and viremia after initiation of HAART. (A) When patients start a 3 drug HAART regimen (yellow, blue and green rectangles), plasma virus levels undergo triphasic decay, ultimately plateauing below the limit of detection of clinical assays. Boxes indicate clinical assays (filled boxes, detectable viremia; open boxes, viremia below 50 copies/ml). Fluctuations in the level of residual viremia can give rise to “blips” that are of no clinical significance. Intensification of HAART by addition of a fourth drug (purple rectangle) does not further reduce residual viremia because this viremia originates from cells infected prior to the initiation of HAART. Despite prolonged suppression of viremia on HAART, viral rebound occurs follow cessation of HAART. (B) The three phases reflect the decay rates of different populations of infected cells. The first phase has a half-life of 1 day and reflects the rapid decay of productively infected CD4⁺ T lymphoblasts. The cells responsible for the second phase, which has a half-life of about 14 days, have not been definitively identified. In the final phase, viral reservoirs are responsible for a very low but stable level of residual viremia. This residual viremia is partly derived from the activation of latently infected resting CD4⁺ T cells and partly from another unknown cell source.

Figure 2

Use of therapeutic vaccination to achieve a functional cure. Vaccination of patients on a 3 drug HAART regimen (yellow, blue and green rectangles) may allow the subsequent control of viremia after cessation of HAART to levels seen in ES. Because the mechanisms for control of HIV-1 replication in ES are not completely clear, the nature of the therapeutic vaccine is still uncertain. However, the stimulation of HIV-1- specific CTL responses is likely to be important.

Figure 3

Use of latency reversing strategies to achieve a sterilizing cure. Reversal of latency in patients on a 3 drug HAART regimen (yellow, blue and green rectangles) may lead to a transient increase in viremia followed by a decrease in the size of the latent reservoir. Latency could be reversed with agents such as the histone deacetylase inhibitor SAHA. This decrease will be difficult to detect with current assays. To ensure that infected cells die after reversal of latency, it may be necessary to combine latency reversing strategies with therapeutic vaccination.