Effects of Genital Tract Inflammation on Human Immunodeficiency Virus Type 1 V3 Populations in Blood and Semen

Investigation of human immunodeficiency virus type 1 (HIV-1) in the genital tract of women is crucial to the development of vaccines and therapies. Previous analyses of HIV-1 in various anatomic sites have documented compartmentalization, with viral sequences from each location that were distinct yet phylogenetically related. Full-length RNA genomes derived from different compartments in the same individual, however, have not yet been studied. Furthermore, although there is evidence that intrapatient recombination may occur frequently, recombinants comprising viruses from different sites within one individual have rarely been documented. We compared full-length HIV-1 RNA sequences in the plasma and female genital tract, focusing on a woman with high HIV-1 RNA loads in each compartment who had been infected heterosexually and then transmitted HIV-1 by the same route. We cloned and sequenced 10 full-length HIV-1 RNA genomes from her genital tract and 10 from her plasma. We also compared viral genomes from the genital tract and plasma of four additional heterosexually infected women, sequencing 164 env and gag clones obtained from the two sites. Four of five women, including the one whose complete viral sequences were determined, displayed compartmentalized HIV-1 genomes. Analyses of full-length, compartmentalized sequences made it possible to document complex intrapatient HIV-1 recombinants that were composed of alternating viral sequences characteristic of each site. These findings demonstrate that the genital tract and blood harbor genetically distinct populations of replicating HIV-1 and provide evidence that recombination between strains from the two compartments contributes to rapid evolution of viral sequence variation in infected individuals.

Section: Discussionmentioning

confidence: 91%

Human Immunodeficiency Virus Type 1 Genomic RNA Sequences in the Female Genital Tract and Blood: Compartmentalization and Intrapatient Recombination

Philpott

Burger

Tsoukas

et al. 2005

“…This suggests the V1/V2 region can reveal more diversity in transmitted variants than the V3 region. Therefore, we believe V1/V2 HTA is a more robust tool for describing a complex viral population than V3 HTA, which we have also used previously in this context (46). The detection of multiple variants in 50% of subjects is a minimum estimate since transmission of two variants with the same V1/V2-HTA pattern would be recorded as a single variant.…”

Section: Discussionmentioning

confidence: 99%

Multiple V1/V2 env Variants Are Frequently Present during Primary Infection with Human Immunodeficiency Virus Type 1

Ritola

Pilcher

Fiscus

et al. 2004

Self Cite

105

Human immunodeficiency virus type 1 (HIV-1) exists as a complex population of multiple genotypic variants in persons with chronic infection. However, acute HIV-1 infection via sexual transmission is a low-probability event in which there is thought to be low genetic complexity in the initial inoculum. In order to assess the viral complexity present during primary HIV-1 infection, the V1/V2 and V3 variable regions of the env gene were examined by using a heteroduplex tracking assay (HTA) capable of resolving these genotypic variants. Blood plasma samples from 26 primary HIV-1-infected subjects were analyzed for their level of diversity. Half of the subjects had more than one V1/V2 viral variant during primary infection, indicating the frequent transmission of multiple variants. This observation is inconsistent with the idea of infrequent transmission based on a small transmitting inoculum of cell-free virus. In chronically infected subjects, the complexity of the viral populations was even greater in both the V1/V2 and the V3 regions than in acutely infected subjects, indicating that in spite of the presence of multiple variants in acute infection, the virus does pass through a genetic bottleneck during transmission. We also examined how well the infecting virus penetrated different anatomical compartments by using the HTA. Viral variants detected in blood plasma were compared to those detected in seminal plasma and/or cerebral spinal fluid of six individuals. The virus in each of these compartments was to a large extent identical to virus in blood plasma, a finding consistent with rapid penetration of the infecting variant(s). The low-probability transmission of multiple variants could be the result of transient periods of hyperinfectiousness or hypersusceptibility. Alternatively, the inefficient transfer of a multiply infected cell could account for both the low probability of transmission and the transfer of multiple variants.Characterization of the earliest stage of human immunodeficiency virus type 1 (HIV-1) infection, primary infection, is critical for gaining a better understanding of HIV-1 pathogenesis. Determining what variants are transmitted and what factors, if any, affect transmission will greatly aid the development of vaccines and other prophylactic therapies (such as microbicides). Primary infection studies may also lead to a better understanding of the role of innate host defense.Primary infection can be roughly subdivided into two phases: acute and early. Peak viremia is reached and resolved during the acute phase while the virus replicates initially in the absence of immune response. Primary infection symptoms begin, on average, 2 weeks after infection (3, 31, 45, 54), most likely the result of the initial immune response. During early primary infection, the immune response matures leading to seroconversion and a steady state of HIV-1 replication (4,6,8,23,28,38,63,66,67). Primary infection ends with seroconversion and stabilization of the Western blot pattern (7, 31). Identifying subjects duri...

“…CD4 ϩ T cell levels, viral loads, and GenBank accession numbers for the analyzed envelope genes are presented in Table 1. Previous analysis of viral RNA sequences in the seminal and blood plasma samples, performed first using a V3-specific heteroduplex tracking assay and then, more recently, using endpoint dilution PCR (i.e., single-genome amplification [SGA]) and sequence analysis, showed that a group of the seminal plasma-derived viral sequences from each of these five subjects formed a lineage genetically distinct from those of virus in the blood of the same subject (7,9). Now we have performed phenotypic analysis of a subset of the fulllength env genes amplified from each subject to determine the entry phenotype with respect to the ability to enter cells efficiently using low levels of CD4.…”

mentioning

confidence: 99%

R5 Macrophage-Tropic HIV-1 in the Male Genital Tract

Bednar

Hauser

et al. 2015

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The entry tropism of HIV-1 Env proteins from virus isolated from the blood and genital tract of five men with compartmentalized lineages was determined. The Env proteins isolated from the genital tract of subject C018 were macrophage-tropic proteins, while the remaining cloned env genes encoded R5 T cell-tropic proteins. The detection of a macrophage-tropic lineage of HIV-1 within the male genital tract strongly suggests that evolution of macrophage-tropic viruses can occur in anatomically isolated sites outside the central nervous system.