Cytopathicity of human immunodeficiency virus type 2 (HIV-2) in human lymphoid tissue is coreceptor dependent and comparable to that of HIV-1

Abstract

Epidemiological studies have shown that human immunodeficiency virus type 2 (HIV-2) is markedly less pathogenic than HIV-1 in vivo. Individuals infected with HIV-2 exhibit a remarkably slow rate of disease development, and these clinical properties have been attributed presumptively to an "attenuated" phenotype of HIV-2 itself. Here, we investigated the impact of coreceptor usage on the cytopathicity of HIV-2 and compared its pathogenic potential with that of HIV-1 in a unique human lymphoid histoculture model. We found that HIV-2 strains, as well as closely related simian immunodeficiency viruses (SIV), displayed mildly or highly aggressive cytopathic phenotypes depending on their abilities to use the coreceptor CCR5 or CXCR4, respectively. A side-by-side comparison of primary X4 HIV-1 and HIV-2 strains revealed similar, high degrees of cytopathicity induced by both HIV types. Furthermore, we found that HIV-2 coreceptor specificity for CCR5 and CXCR4 determined the target cell population for T-cell depletion in lymphoid tissue. Finally, utilization of the alternate coreceptors BOB and Bonzo did not significantly increase the cytopathic properties of HIV-2. These findings demonstrate that coreceptor preference is a key regulator of target cell specificity and the cytopathic potential of HIV-2, with indistinguishable rules compared with HIV-1. Moreover, HIV-2 strains are not characterized by an intrinsically lower cytopathicity than HIV-1 strains. Therefore, direct cytopathic potential per se does not explain the unique behavior of HIV-2 in people, highlighting that other unknown factors need to be elucidated as the basis for their lesser virulence in vivo.

FIG. 1

The cytopathic phenotype of HIV-2 is linked to coreceptor specificity in ex vivo lymphoid tissue. (A) CD4⁺ T-cell depletion in adenoid cultures by various HIV-2 strains and two HIV-1 recombinants was assessed by FACS analysis on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with the SEM. Previously reported coreceptor specificities are indicated (7, 26, 28, 29). (Inset) Viral replication of the HIV-2 isolates was monitored by assessing accumulation of p27 in the culture supernatant between successive medium changes. (B) In the same infection, depletion within the CCR5⁺ and the CCR5⁻ subsets of CD4⁺ T cells was analyzed by multiparameter FACS on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with the SEM for CCR5⁺ and CCR5⁻ T cells.

FIG. 2

Comparable and progressive depletion of CD4⁺ T cells by multitropic primary isolates of HIV-1 and HIV-2 in ex vivo tonsil cultures. Ex vivo tonsil cultures were inoculated with the primary HIV-1 isolate 12/86 and the primary HIV-2 isolate 7924A, and CD4⁺ T-cell depletion was assessed by FACS analysis on subsequent days (3, 6, 9, 13, and 16) postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM (∗, n = 2).

FIG. 3

An HIV-2 strain with attenuated cytopathicity in vitro displays the typical depletion phenotype of R5 strains. (A) Tonsil histocultures were inoculated with HIV-2 ST/SXB1, X4 HIV-2 isolate 7924A, and R5 HIV-2 isolate SLRHC. CD4⁺ T-cell depletion was assessed on day 12 postinfection. Previously reported coreceptor specificities are indicated (11, 28). Shown are mean relative CD4/CD8 ratios (n = 3) with SEM. (Inset) Viral replication was monitored by assessing accumulation of p27 in the culture supernatant between successive medium changes. (B) In the same infection, depletion within the CCR5⁺ and the CCR5⁻ subsets of CD4⁺ T cells was analyzed by multiparameter FACS on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM.

FIG. 4

Mild depletion of CD4⁺ T cells by recombinant strains of SIVmac in ex vivo lymphoid tissue. (A) Ex vivo tonsil cultures were inoculated with recombinant strains SIVmac239, SIVmac316, and SIVmac239PS and primary HIV-2 isolates A1958 and 7924A. CD4⁺ T-cell depletion was assessed by FACS on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM. Coreceptor preferences are indicated as described previously (7, 12, 28, 30). (Inset) Viral replication was monitored by assessing accumulation of p27 in the culture supernatant between successive medium changes. (B) In the same infections, T-cell depletion analysis was stratified into CCR5⁺ and CCR5⁻ CD4⁺ T-cell subsets by multiparameter FACS. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM for CCR5⁺ and CCR5⁻ T cells.

FIG. 5

Mild depletion of CD4⁺ T cells by primary SIVsmm isolates in ex vivo lymphoid tissue. (A) Ex vivo tonsil cultures were inoculated with primary SIVsmm isolates FKl and FBo. CD4⁺ T-cell depletion was assessed by FACS on day 12 postinfection. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM. (Inset) Viral replication was monitored by assessing accumulation of p27 in the culture supernatant between successive medium changes. (B) In the same infections, T-cell depletion analysis was stratified into CCR5⁺ and CCR5⁻ CD4⁺ T-cell subsets by multiparameter FACS. Shown are mean relative CD4/CD8 ratios (n = 3) with SEM for CCR5⁺ and CCR5⁻ T cells. (C) Coreceptor preferences of SIVsmm isolates FKl and FBo were established by infection of GHOST cells stably expressing CD4 together with various coreceptors. Shown is usage of alternative coreceptors relative to that of CCR5.