Semen-Specific Genetic Characteristics of Human Immunodeficiency Virus Type 1 env

Abstract

Human immunodeficiency virus type 1 (HIV-1) in the male genital tract may comprise virus produced locally in addition to virus transported from the circulation. Virus produced in the male genital tract may be genetically distinct, due to tissue-specific cellular characteristics and immunological pressures. HIV-1 env sequences derived from paired blood and semen samples from the Los Alamos HIV Sequence Database were analyzed to ascertain a male genital tract-specific viral signature. Machine learning algorithms could predict seminal tropism based on env sequences with accuracies exceeding 90%, suggesting that a strong genetic signature does exist for virus replicating in the male genital tract. Additionally, semen-derived viral populations exhibited constrained diversity (P < 0.05), decreased levels of positive selection (P < 0.025), decreased CXCR4 coreceptor utilization, and altered glycosylation patterns. Our analysis suggests that the male genital tract represents a distinct selective environment that contributes to the apparent genetic bottlenecks associated with the sexual transmission of HIV-1.Most human immunodeficiency virus (HIV) transmission events globally occur via mucosal exposure to male genital secretions carrying the virus (34,46). Although the risk of sexual HIV transmission correlates with the amount of virus present in the blood of the source partner (36), the correlation between the viral load in the blood and genital compartment is inconsistent (3,23,24). The biological determinants that influence the transmissibility of different viral variants from within the genital tract of the HIV-infected source are still incompletely understood. Since transmitted virus represents the initial virus that the immune system encounters, the understanding of its composition will be critical in our attempts to develop a successful HIV vaccine (1,7,54).HIV in each chronically infected person exists as a diverse population of related genetic variants (5,12,20). Anatomic compartmentalization of these variants has been described in blood, lung, central nervous system, and genital tract (10,16,17,20,21,32,41,50,53). Male genital tract tissues (e.g., the prostate, seminal vesicles, and epididymis) serve as sites of viral replication and are likely to differ from peripheral tissues in immunological surveillance, target cell characteristics, and efficiencies of drug penetration (10,17,43). Virus replicating within the male genital tract could therefore develop distinct, compartment-specific characteristics in response to these local selective pressures (10,16,17,20,21,32,41,50,53). Although genetic differences between blood-and semen-derived HIV in an individual have been documented, a seminal signature sequence remains elusive (6, 10). This failure to identify a signature sequence could be attributable to the fact that previous efforts mainly focused on proviral DNA sequences, which often represent archival viral genotypes rather than contemporary, actively replicating variants (4, 44).We investigated viral genetic...

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

“…Sequences derived from HIV RNA recovered from the semen of men under suppressive HAART were found to be distinct from those from blood (6). This is similar to the compartmentalization of viral strains between blood and semen described in a subset of therapy-naive men (39)(40)(41) and macaques (42). Such a compartmentalization indicates that HIV/simian immunodeficiency virus (SIV) contaminating the semen of those individuals arises from the production of viral strains within the male genital tract (MGT) with distinct evolution from blood strains.…”

Measuring the latent reservoir in vivo

“…In addition to the large amount of lymphoid tissue in the body, two anatomic compartmentsthe CNS and the genital tract -have been shown to permit compartmental evolution and occasionally escape from the effective suppression of replication as measured in the blood (92)(93)(94)(95)(96). These two anatomic compartments differ from the rest of the body in being both pharmacologic and immunologic sanctuaries for HIV, and, in the case of the CNS, containing a large proportion of cells of the macrophage lineage.…”

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

“…Although semen represents the foremost vector of HIV-1 dissemination, 1 the precise origins of the infected leukocytes and free viral particles contaminating the seminal plasma remain unclear. Phylogenetic studies have established that HIV in semen arises from local sources within the male genital tract and/or from passive diffusion via the blood [2][3][4] (previous references in Le Tortorec and Dejucq-Rainsford 5 ). The existence of productive sources in the male genital tract is further substantiated through observations of several differences between blood and semen, including i) detection of persistent infectious HIV in the semen of 5% to 30% of men with undetectable blood viral load receiving fully suppressive antiretroviral therapy [5][6][7][8][9] ; ii) higher viral load in semen in a subpopulation of treatment-naïve men 10 ; iii) different rates, kinetics of emergence, and diversity of drug-resistant strains 4,11,12 ; and iv) different ratio of infected versus noninfected leukocytes.…”