Impaired replication capacity of acute/early viruses in persons who become HIV controllers - PubMed (original) (raw)

. 2010 Aug;84(15):7581-91.

doi: 10.1128/JVI.00286-10. Epub 2010 May 26.

Zabrina L Brumme, Mark A Brockman, Pamela Rosato, Jennifer Sela, Chanson J Brumme, Florencia Pereyra, Daniel E Kaufmann, Alicja Trocha, Brian L Block, Eric S Daar, Elizabeth Connick, Heiko Jessen, Anthony D Kelleher, Eric Rosenberg, Martin Markowitz, Kim Schafer, Florin Vaida, Aikichi Iwamoto, Susan Little, Bruce D Walker

Affiliations

Impaired replication capacity of acute/early viruses in persons who become HIV controllers

Toshiyuki Miura et al. J Virol. 2010 Aug.

Abstract

Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P = 0.018). Moreover, of two HLA-B57-positive (B57(+)) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57(+) donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.

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Figures

FIG. 1.

FIG. 1.

Kinetics of plasma virus loads during acute/early phase of infection in individuals who subsequently achieve viremia control (<2,000 RNA copies/ml). (A) Data for six controllers after primary infection (C-PI) who achieved elite control (EC; <50 RNA copies/ml) during the follow-up period. Each line represents the plasma virus loads of an individual patient; the dashed line indicates 2,000 RNA copies/ml. The blue line shows data for C-PI_18, who achieved <50 RNA copies/ml after 600 days post-EDI and, therefore, displayed >50 RNA copies/ml during the period shown in the figure. (B) Data for twelve C-PI who remained viremic during the follow-up period. Each line represents the plasma virus loads of an individual patient; the dashed line indicates 2,000 RNA copies/ml. VC, viremic controllers. (C) Data for C-PI_12, who achieved elite control after 700 days post-EDI after experiencing a blip in viremia. (D) Data for C-PI_04, who achieved elite control after 470 days post-EDI and also experienced virologic escape after 1,500 days post-EDI. (E and F) Data for C-PI_02 and 03, who experienced virologic escape. ART, antiretroviral therapy.

FIG. 2.

FIG. 2.

Proportions of the individuals expressing protective HLA class I alleles. (A) Proportions of individuals expressing HLA-B57 among controllers after primary infection (C-PI), noncontrollers after primary infection (NC-PI), and chronic HIV controllers (C-chronic). (B) Proportions of individuals expressing protective HLA class I alleles (B13, B27, B51, and B57/B*1516/B*1517/B*5801) among C-PI, NC-PI, and C-chronic.

FIG. 3.

FIG. 3.

Replication capacities of chimeric NL4-3 viruses carrying gag-protease derived from the acute phase of infection in controllers and noncontrollers. Replication capacities were compared between clade B-infected C-PI (n = 15) and NC-PI (n = 45). Average results of duplicate experiments for each virus normalized to the replication capacity of wild-type (wt) NL4-3 virus were plotted (expressed as the slope of the natural log of viral spread between days 3 and 6; see Materials and Methods). (A) Data for all of the chimeric viruses derived from individuals in acute/early phase of infection. The pink dots indicate viruses carrying protease inhibitor (PI) resistance mutations. (B) Data are the same as in the analysis shown in panel A, but the data for viruses derived from the NC-PI are stratified according to phase of infection (acute or early). Horizontal lines show medians of the results.

FIG. 4.

FIG. 4.

Proportions of individuals diagnosed during acute/early phase and carrying viral strains with major drug resistance mutations (see Materials and Methods) are shown. (A) Data for individuals infected with strains with major PI, NRTI, and NNRTI resistance mutations. (B) Data for individuals infected with multiclass drug-resistant strains. (C) Data for individuals without protective HLA class I alleles infected with strains with major PI, NRTI, and NNRTI resistance mutations. (D) Data for individuals without protective HLA class I alleles infected with multiclass drug-resistant strains.

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