CD8+ T cell-mediated CXC chemokine receptor 4-simian/human immunodeficiency virus suppression in dually infected rhesus macaques

Abstract

We coinfected rhesus macaques with CXC chemokine receptor 4- and CC chemokine receptor 5-specific simian/human immunodeficiency viruses (SHIVs) to elucidate the basis for the early dominance of R5-tropic strains seen in HIV-infected humans. We found no intrinsic barrier to the transmission and dissemination of high-dose X4-SHIV in the dually infected macaques. In animals that maintained a viral set point, the R5 virus predominated. The time of appearance of R5 dominance coincided with the development of virus-specific immunity (3-6 weeks postinfection), suggestive of differential immune control of the two viruses. Indeed, after depletion of CD8+ T cells in the coinfected animals, X4 virus emerged, supporting the concept that differential CD8+ T cell-mediated immune control of X4- and R5-SHIV replication is responsible for the selective outgrowth of R5 viruses. These findings provide critical insights into a key question related to HIV pathogenesis and have important implications for the development and testing of antiviral vaccines and therapeutics.

Fig. 1.

Viral replication, T cell subsets, and viral genotype in i.v. dually infected macaques. (i) Peripheral blood was collected in EDTA at designated time intervals and separated into plasma and cellular components. The absolute copies of viral RNA per ml of plasma (viremia, thick line) were determined by branched-DNA analysis (Bayer Diagnostics). The absolute number of CD3⁺CD4⁺ (▴) or CD3⁺CD8⁺(▵) cells per μl of blood as determined by Tru-Count FACS analysis. +, time that macaques were killed due to development of clinical symptoms of SAIDS. (ii) Percentage of CCR5- (•) or CXCR4- (○) specific env clones amplified by RT-PCR from plasma.

Fig. 2.

Virologic, immunologic, and genotypic measurements in IVAG dually infected macaques. The symbols are as described for Fig. 1. *, Presence of recombinant virus.

Fig. 3.

Changes in genotype of replicating virus after CD8⁺ T cell depletion in dually infected macaques. AJ12 was administered the mAb cM-T807 on days 0, 3, and 7 (arrows). Viral load and T cell subsets (i) and viral genotype (ii) were analyzed as described for Fig. 1.

Fig. 4.

Dominance of R5-SHIV_SF162P3 after i.v. inoculation of macaques. The symbols are as described for Fig. 1.

Fig. 5.

X4-SHIV_SF33A emerged in i.v. dual-infected macaques after CD8⁺ T cell depletion. Viral load and T cell subsets (i) and viral genotypes (ii) were determined as described for Fig. 1. The arrows indicate time of administration of the anti-CD8 mAb cM-T807.