Infectious cellular load in human immunodeficiency virus type 1 (HIV-1)-infected individuals and susceptibility of peripheral blood mononuclear cells from their exposed partners to non-syncytium-inducing HIV-1 as major determinants for HIV-1 transmission in homosexual couples

Abstract

To study risk factors for homosexual transmission of human immunodeficiency virus type 1 (HIV-1), we compared 10 monogamous homosexual couples between whom transmission of HIV-1 had occurred with 10 monogamous homosexual couples between whom HIV-1 transmission had not occurred despite high-risk sexual behavior. In the group of individuals who did not transmit virus, peripheral cellular infectious load was lower and the CD4+ T-cell counts were higher than in the group of transmitters. HIV-1 RNA levels in serum did not differ between transmitters and nontransmitters. Compared with peripheral blood mononuclear cells (PBMC) from normal healthy blood donors, 8 of 10 nonrecipients and only 3 of 8 recipients had PBMC with reduced susceptibility to in vitro infection with non-syncytium-inducing (NSI) HIV-1 variants isolated from either their respective partners or an unrelated individual. No difference in susceptibility was observed for infection with a syncytium-inducing variant. Among the individuals who had PBMC with reduced susceptibility, five nonrecipients and one recipient had PBMC that were equally or even less susceptible to NSI variants than PBMC that had low susceptibility and that were derived from healthy blood donors that were heterozygous for a 32-bp deletion in the CCR5 gene (CCR5 delta32). Three of these individuals (all nonrecipients) had a CCR5 delta32 heterozygous genotype themselves, confirming an association between low susceptibility to NSI variants and CCR5 delta32 heterozygosity. All three recipients with less susceptible PBMC had partners with a high infectious cellular load; inversely, both nonrecipients with normally susceptible PBMC had partners with a very low infectious cellular load. These results suggest that a combination of susceptibility of target cells and inoculum size upon homosexual exposure largely determines whether HIV-1 infection is established.

FIG. 1

Peripheral viral load and CD4⁺ T-cell counts in nontransmitters and transmitters. (a) Cellular infectious load, expressed as log TCID per 10⁶ CD4⁺ T cells. (b) RNA load in serum, expressed as log RNA copies per milliliter of serum. (c) Mean CD4⁺ T-cell counts per microliter of blood. For nontransmitters, PBMC and serum samples obtained as close as possible to the moment of entry into the ACS were analyzed. For transmitters, PBMC and serum samples obtained as close as possible to the date of seroconversion of the recipients were analyzed. PBMC and serum samples were mostly derived from the same visit (in 16 cases) or, maximally, 2 months apart. The mean CD4⁺ T-cell counts were calculated from the CD4⁺ T-cell counts on the first three visits after the moment of entry for the nontransmitters and from the CD4⁺ T-cell counts on the three visits closest to the date of seroconversion of the recipients for the transmitters. Bars indicate median values. ns, not significant.

FIG. 2

Analysis of relative susceptibilities of recipient and nonrecipient PBMC to corresponding transmitter and nontransmitter HIV-1 variants. Virus variants isolated from transmitters and nontransmitters were titrated (expressed as TCID₅₀ per milliliter of supernatant) on PHA-stimulated PBMC from the respective recipients and nonrecipients and on PHA-stimulated PBMC from five healthy blood donors. Within each panel, the different symbols represent different virus variants derived from the specific transmitter or nontransmitter. The virus titers on PBMC from blood donors 1 and 3 (bd 1 + 3) and blood donors 2, 4, and 5 (bd 2,4+5) are shown as separate groups and are compared with the virus titers on PBMC from the respective nonrecipients (nr) and recipients (r) of couple D10 (a), couple C1 (b), couple D3 (c), and couple C4 (d). −, +, ++, and +++ indicate the relative susceptibilities of the recipient and nonrecipient PBMC.

FIG. 3

Relative susceptibilities of PBMC from nonrecipients and recipients to partner and unrelated NSI and SI HIV-1 variants. (a) Relative susceptibilities of PBMC from each nonrecipient and recipient to HIV-1 variants isolated from their partners are plotted. Different symbols indicate individuals having PBMC with low susceptibility (white), intermediate susceptibility (gray), and normal to high susceptibility (black). (b and c) PBMC from recipients and nonrecipients were stratified by their susceptibilities to partner HIV-1 variants and analyzed for their susceptibilities (expressed as log TCID₅₀ per milliliter of virus stock) to an unrelated NSI variant (b) and an unrelated SI variant (c). Bars indicate median values. ns, not significant.