François Clavel

Laboratoire de Recherche Antivirale INSERM U82, Hôpital Bichat-Claude Bernard, Paris, France

Resistance mutations that are selected in the course of virologic failure of antiretroviral therapy in HIV disease confer a high selective growth advantage to the virus in the presence of antiretroviral drugs. However, some mutations or combinations of mutations are deleterious for the overall replicative capacity of the virus, which is sometimes referred to as HIV fitness. These effects are particularly perceptible for mutations in the HIV protease that mediate resistance to protease inhibitors, leading to abnormal patterns of cleavage of the precursors of HIV structural and enzymatic proteins. As a consequence, mutant viral particles display a significantly reduced infectivity. Interestingly, these defects can be partially or, in some instances completely, compensated by secondary mutations emerging either in PR or in some of its natural Gag substrates. Some resistance mutations in reverse transcriptase can also impair HIV drug-free fitness, but generally to a lesser extent. The impact of the reduction of HIV replicative potential on the clinical and immunological profile of the disease is not fully understood. Several lines of evidence suggest that, indeed, loss of viral fitness is translated into a parallel loss in HIV virulence. In patients failing antiretroviral therapy, a disconnection between the high levels of resistant virus replication and the persistence of high CD4 counts has been described. This disconnection appears to fade with time, but can persist for about 3 years after the start of treatment failure. In patients with established HIV drug resistance in which treatment is interrupted, the resistant virus is most often replaced by a wild-type, drug sensitive counterpart, a sign that its replicative fitness is reduced. In parallel, a strong rebound in viremia, associated with a marked decrease in CD4 counts is observed, a sign that wild-type virus has also recovered higher virulence characteristics. The mechanisms through which impaired HIV fitness can lead to higher CD4 counts in spite of high virus replication levels is still debated. In the SCID-hu mouse model, protease inhibitor-resistant viruses fail to replicate in thymic implants while they replicate almost normally in cultures of stimulated PBLs, suggesting that resistance-associated replication impairment can strikingly differ according to the cell or tissue compartment that harbors the virus. In treated patients displaying a disconnected profile, high CD4 counts appear to be indeed associated with a higher thymic output, as measured by quantitative analysis of the amounts of TRECs (T cell receptor excision circles) a marker of recent thymic emigration of peripheral T cells. These results suggest that although combined with multiple other parameters of immune reconstitution, the loss of viral fitness that can result from some patterns of resistance mutations may reduce HIV pathogenicity and disease progression.