Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers

Abstract

BACKGROUND. Human immunodeficiency virus (HIV) elite controllers are able to control infection with HIV-1 spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although low frequencies of HIV-infected peripheral CD4(+) T cells have been reported in this group, it remains unclear to what extent these are due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. METHODS. We assessed proviral DNA levels, autologous viral growth from and infectability of in vitro activated, CD8(+) T cell-depleted CD4(+) T cells from HIV elite controllers (mean viral load, <50 copies/mL), viremic controllers (mean viral load, <2000 copies/mL), chronic progressors, and individuals receiving highly active antiretroviral therapy. RESULTS. Although we successfully detected autologous virus production in ex vivo activated CD4(+) T cells from all chronic progressors and from most of the viremic controllers, we were able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4(+) T cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to those in CD4(+) T cells from HIV-uninfected subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contribute to difficulty in isolation of virus. CONCLUSIONS. These data indicate that elite control is not due to inability of activated CD4(+) T cells to support HIV infection, but the relative contributions of host and viral factors that account for maintenance of low-level infection remain to be determined.

Fig 1

Autologous virus replication in activated autologous CD4+ T-cells A. Kinetics of autologous virus replication (log₁₀ p24 in pg/ml) among EC, VC, progressors and HAART treated individuals B. Mean log₁₀ p24 levels (pg/ml) after 10 and 20 days among EC, VC (§ HLA B5701/B5703; # HLA B2705/B5701), progressors and HAART treated individuals

Fig 2

Proviral loads (DNA copies/10⁶ PBMCs) among EC, VC, progressors and HAART treated individual

Fig 3

Replication of an HIV-1 clinical isolate in activated CD4+ T-cells of 14 elite controllers.

Fig 4

Replication of (A) the X4 tropic HIV-1 strain NL4-3 and (B) the R5 tropic HIV-1 strain JRCSF in activated CD4+ T-cells of 12 elite controllers and 12 HIV negative individuals (MOI 0.01). Shown are mean log₁₀ p24 levels (pg/ml) at day 7.