Selective inhibition of syncytium-inducing and nonsyncytium-inducing HIV-1 variants in individuals receiving didanosine or zidovudine, respectively.

Abstract

By studying changes in the clonal composition of HIV-1 populations during the first weeks of zidovudine (ZDV) treatment before the development of ZDV resistance-conferring mutations, we demonstrated previously a selective inhibition of nonsyncytium-inducing (NSI) HIV-1, even when present as coexisting population in individuals also harboring syncytium-inducing (SI) HIV-1. In this study, we observed the opposite in individuals receiving didanosine (ddI) treatment. In these individuals ( n ϭ 7) a median Ϫ 0.98 log change (range Ϫ 1.55-0.08) in infectious cellular SI load was observed, whereas the coexisting NSI load was only minimally affected (median Ϫ 0.15 log, range Ϫ 1.27-0.50; P ϭ 0.03). The virus phenotype-dependent treatment responses were independent of the clonal composition of HIV-1 populations at baseline. Individuals treated with a combination of ZDV and ddI revealed an equal decline of both NSI and SI infectious cellular load ( n ϭ 4; NSI: median Ϫ 1.55 log, range Ϫ 2.19 to Ϫ 1.45; SI: median Ϫ 1.47 log, range Ϫ 1.81 to Ϫ 0.86; P ϭ 0.56).To test the hypothesis that the previously reported optimal activation of ZDV and ddI in activated and resting T cells, respectively, in combination with the differential T cell tropism of NSI and SI HIV-1 is the basis for the observed virus phenotype specific efficacy of nucleoside analogs, we studied the effect of treatment with a protease inhibitor that does not require intracellular activation. Individuals receiving ritonavir ( n ϭ 4) indeed showed equal declines in NSI and SI infectious cellular load (NSI: median Ϫ 2.37 log, range Ϫ 2.59 to Ϫ 2.16; SI: median Ϫ 2.82 log, range Ϫ 3.14 to Ϫ 2.50; P ϭ 0.25). Our data suggest HIV-1 phenotype as an additional parameter in the design of optimal treatment regimens. (

Differential coreceptor expression allows for independent evolution of non–syncytium-inducing and syncytium-inducing HIV-1

“…This is in agreement with previous findings showing a differential effect of NSI and SI HIV-1 in response to monotherapy with AZT and ddI (68), nucleoside analogues that depend on phosphorylation by cellular kinases for their activity.…”

CXCR4-Using HIV Type 1 Variants Are More Commonly Found in Peripheral Blood Mononuclear Cell DNA Than in Plasma RNA

“…Several reports suggest a different activity of antiretroviral drugs on viruses with different phenotypes. [42][43][44][45] Though we cannot exclude an influence of the treatment on the distribution of X4 and R5 sequences in the 3 treated individuals, this cannot explain the overall tendency observed in the majority of the patients tested.…”

Viral Replication Capacity as a Correlate of HLA B57/B5801-Associated Nonprogressive HIV-1 Infection

“…However, there is evidence that the viral quasispecies in plasma and the replication-competent HIV-1 variants in productively infected cells are closely related, if not the same viral compartments. Indeed, the kinetics of viral load changes and the emergence of drug resistance mutations in plasma/serum and productively infected cells are highly correlated (45)(46)(47). Moreover, an interesting aspect of our approach is that it allowed us to directly compare replication capacity in relation to sequence diversity.…”