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

Abstract

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.

Frequent Intrapatient Recombination between Human Immunodeficiency Virus Type 1 R5 and X4 Envelopes: Implications for Coreceptor Switch

“…3 and Table 2). Taking these observations into consideration (37) and the fact that both double infection (4,14) and intrapatient recombination are commonly observed for HIV-1 in vivo (3,14,19,34,48), we feel confident that the majority of our recombinant sequences originated in vivo (37).…”

“…Recombination events between viruses of different subtypes of the major (M) group have resulted in a number of stable circulating recombinant forms (20,21,29,47). Furthermore, recombination between viruses isolated from different anatomical sites from one individual has been reported (19,34). Establishment of recombinant viruses within an infected individual may lead to serious consequences, for example, due to the rapid spread of drug resistance in the virus population (18) and accelerated progression toward AIDS (26).…”

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

“…Intrapatient variation in the nature of reservoirs has been reported. Differing selective pressures likely contribute to genetic variation among compartments' HIV-1 populations and may limit how much of the genetic heterogeneity within individual patients can serve as sources of intrapatient recombination (209,258).…”

Comparative Study of Methods for Detecting Sequence Compartmentalization in Human Immunodeficiency Virus Type 1

“…If trafficking and gene flow between viral subpopulations is significantly restricted, then each subpopulation can become genetically distinct from others, i.e., compartmentalized. Compartmentalization has been defined in different ways, for example, as genetic heterogeneity between subpopulations (1), as the result of independent micro-evolution (8), as the result of restricted viral gene flow (39), or as the presence of distinct but phylogenetically related genotypes (43). Various mechanisms can contribute to the compartmentalization of HIV populations.…”

“…HIV type 1 (HIV-1) populations isolated from the genital tract in both men and women have been reported as compartmentalized (12,29,43,45,47,48,65,73) when compared to the viruses isolated from the blood or lymphoid tissue. Since the most common route of HIV transmission worldwide is genital exposure (52), the study of HIV populations replicating in the genital tract will help us develop strategies to prevent transmission.…”