HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 POPULATIONS IN BLOOD AND SEMEN

Genital secretions are the source of a majority of human immunodeficiency virus type 1 (HIV-1) infections. Culturable HIV-1 (23, 59) and proviral DNA (21, 37) have been detected in the nonspermatozoal mononuclear cell fraction of semen, which includes CD4+ lymphoid cells, monocytes, and macrophages (2, 54). Cell-free virions, measured as viral RNA, are also found in seminal fluid (20, 21, 37). Heteroduplex tracking analyses of PCR-amplified HIV-1 env sequences from donor-recipient sexual transmission pairs revealed distinctions between viral variant populations in plasma, peripheral blood mononuclear cells (PBMC), seminal cells, and seminal fluid (62). In three of five cases, virus in semen mononuclear cells was the most closely related to that transmitted to the recipient, and hence these cells were implicated as a likely vehicle for transmission (62). Drug resistance mutations in HIV populations are also unequally distributed in the blood and semen (29). Genetic differences were also found between proviral variants in peripheral blood and those in genital secretions in one study of women infected with HIV-1 envelope sequence subtypes A and D (41). Distinctions between viral populations in other anatomical sites have also been noted (14, 24, 27). Early following infection with envelope subtype B virus via homosexual or perinatal contact, intravenous drug use, and blood transfusion, individuals harbor viruses in their blood that are homogeneous over the V3 region of the envelope protein (8, 10, 30, 36, 39, 47, 57, 60, 61). V3 loop sequences are also relatively conserved between individuals early following infection and correspond to a macrophage-tropic or non-syncytium-inducing (NSI) signature sequence (6, 35, 47, 53, 60), despite the fact that the donor may harbor a highly differentiated virus population in the blood (56, 62). A simultaneously greater amount of viral genetic diversity has been reported in the gag gene at these early times (60, 61). This observation led to the hypothesis that selection may occur for the dissemination of a subset of variants with a particular envelope-mediated phenotype, possibly macrophage tropism. With the recognition of the existence of HIV coreceptors, this could also correspond to a tropism for coreceptors of the CC-chemokine receptor class or exclusion of the viruses that utilize CXCR-4 (1, 12, 13, 18). It is also possible that macrophage-tropic HIV variants are more likely to be found in, and thereby transmitted from, the genital compartment, since, in contrast to the balance in the blood, a greater number of monocytes and macrophages are found in semen (2, 54). In contrast to other modes of transmission, complex HIV-1 envelope sequence populations have been reported in one study of recently seroconverting women heterosexually infected with subtype A or D (41). Sexual transmission from men requires infection of cells in or migrating to seminal fluid or cell-free transfer of virus to this compartment. A comparison of blood and semen viral populations may therefore indicate whether virus in the male genital tract commingles with that of blood or corresponds to a compartmentalized subset or distinct population of variants. In this report, we describe a cross-sectional study of proviral sequences in peripheral blood and nonspermatozoal semen cells from five HIV-1 subtype B-infected individuals. Strong evidence for nonrandom distribution of virus variants between the two compartments and of a more restricted founder population accounting for the semen provirus population was found in all three of the patients who also harbored virus with mutations characteristic of a syncytium-inducing (SI) viral genotype. However, no evidence was found for restriction of the SI genotype from the semen.