Relationship of human immunodeficiency virus type 1 sequence heterogeneity to stage of disease.

McNearney, Terry A.; Hornickova, Zuzana; Markham, Richard B.; Birdwell, Anahid; Arens, Max Q.; Saah, Alfred J.; Ratner, Lee

doi:10.1073/pnas.89.21.10247

Cited by 205 publications

(155 citation statements)

References 53 publications

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“…Since the viruses isolated early after sexual transmission are mainly R5 viruses (32,60,67), our data suggest that the properties conferring virus replication early after transmission are distinct from those conferring cell-free virus transcytosis through the genital epithelium. Thus, it is likely that factors other than CCR5 usage on PGECs dictate R5 virus predominance during the early steps of HIV-1 colonization.…”

Section: Discussionmentioning

confidence: 89%

Cell-Free Human Immunodeficiency Virus Type 1 Transcytosis through Primary Genital Epithelial Cells

Bobardt

Chatterji

Selvarajah

et al. 2007

J Virol

145

193

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Although the transport of human immunodeficiency virus type 1 (HIV-1) through the epithelium is critical for HIV-1 colonization, the mechanisms controlling this process remain obscure. In the present study, we investigated the transcellular migration of HIV-1 as a cell-free virus through primary genital epithelial cells (PGECs). The absence of CD4 on PGECs implicates an unusual entry pathway for HIV-1. We found that syndecans are abundantly expressed on PGECs and promote the initial attachment and subsequent entry of HIV-1 through PGECs. Although CXCR4 and CCR5 do not contribute to HIV-1 attachment, they enhance viral entry and transcytosis through PGECs. Importantly, HIV-1 exploits both syndecans and chemokine receptors to ensure successful cell-free transport through the genital epithelium. HIV-1-syndecan interactions rely on specific residues in the V3 of gp120 and specific sulfations within syndecans. We found no obvious correlation between coreceptor usage and the capacity of the virus to transcytose. Since viruses isolated after sexual transmission are mainly R5 viruses, this suggests that the properties conferring virus replication after transmission are distinct from those conferring cell-free virus transcytosis through the genital epithelium. Although we found that cell-free HIV-1 crosses PGECs as infectious particles, the efficiency of transcytosis is extremely poor (less than 0.02% of the initial inoculum). This demonstrates that the genital epithelium serves as a major barrier against HIV-1. Although one cannot exclude the possibility that limited passage of cell-free HIV-1 transcytosis through an intact genital epithelium occurs in vivo, it is likely that the establishment of infection via cell-free HIV-1 transmigration is a rare event.

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Section: Discussionmentioning

confidence: 89%

Cell-Free Human Immunodeficiency Virus Type 1 Transcytosis through Primary Genital Epithelial Cells

Bobardt

Chatterji

Selvarajah

et al. 2007

J Virol

145

193

View full text Add to dashboard Cite

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“…Although the genetic diversity, both within subpopulations and as a whole, is likely to be lower than their equilibrium values [because of the relatively genetically homogeneous viral population at the initial bottleneck of infection (6,(55)(56)(57)(58)], the ratio of the two, as measured by F ST , reaches its equilibrium value relatively rapidly, and hence estimates of F ST , and our conclusions based on them are not expected to be greatly affected by the bottleneck of infection.…”

Section: Discussionmentioning

confidence: 99%

Genetic drift and within-host metapopulation dynamics of HIV-1 infection

Frost

Dumaurier

Wain‐Hobson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

126

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Most HIV replication occurs in solid lymphoid tissue, which has prominent architecture at the histological level, which separates groups of productively infected CD4 ؉ cells. Nevertheless, current population models of HIV assume panmixis within lymphoid tissue. We present a simple ''metapopulation'' model of HIV replication, where the population of infected cells is comprised of a large number of small populations, each of which is established by a few founder viruses and undergoes turnover. To test this model, we analyzed viral genetic variation of infected cell subpopulations within the spleen and demonstrated the action of founder effects as well as significant variation in the extent of genetic differentiation between subpopulations among patients. The combination of founder effects and subpopulation turnover can result in an effective population size much lower than the actual population size and may contribute to the importance of genetic drift in HIV evolution despite a large number of infected cells.H IV has an enormous evolutionary potential because of the combination of a high mutation rate (Ϸ3 ϫ 10 Ϫ5 substitutions͞site͞generation; ref. 1), a short generation time (Ϸ2.6 days; refs. 2 and 3), and a large number of infected cells within the host (10 7 -10 8 infected cells; ref. 4). Many analyses of the pattern of nucleotide substitution in the viral env gene have detected evolution in response to positive selection (5-16), although relatively few studies have linked these patterns of viral genetic variation to selection by defined immune responses or for changes in viral phenotype associated with coreceptor usage. In the presence of antiretroviral agents that target viral protease and reverse transcriptase, positive selection has been described in numerous studies, which demonstrate convergent evolution in different individuals of mutations that confer drug resistance (17)(18)(19)(20). Although specific mutations have been identified with escape from immune responses and escape from antiretrovirals, viral genetic variation reflects more than just these focused positive selection pressures and may reflect more subtle processes of within-host competition between viruses for higher replicative potential.Despite an enormous potential to respond to selection, there can be substantial differences between infected individuals in the evolution of drug resistance. For example, the frequency of single drug-resistant mutants in viral protease and reverse transcriptase before therapy can vary dramatically between hosts (21-23), apparently by random. Indirect observations of the apparently stochastic way in which multiply resistant mutants emerge during therapy are also consistent with a role of genetic drift (18,24,25). In addition, three studies of the evolution of env gene sequences have found substantially lower genetic variation than expected for a population of the order of 10 7 (24,26,27). These studies estimated the ''effective'' population size to be of the order of 10 3 , reflecting the high relatedness be...

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“…Recent studies suggest that regardless of the route of transmission (mucosal, intravenous, drug use, transfusion of blood products), the HIV that is transmitted is genotypically fairly homogenous (Cichutek et al, 1991;McNearney et al, 1992;Pang et al, 1992) and phenotypically macrophage-tropic. This is in direct contrast to the lymphocyte-tropic viruses that predominate later in infection (Cichutek et al, 1991;McNearney et al, 1992;Pang et al, 1992;Wolfs et al, 1992;Wolinsky et al, 1992;Zhang et al, 1993;Zhu et al, 1993). Since macrophagetropism appears to be a prerequisite for the development of neurological disease, this suggests that the virus that is transmitted and replicating during acute infection has the capability of entering and potentially replicating in the brain quite early in infection.…”

Section: Viral Contributions To Aids Dementiamentioning

confidence: 99%

SIV infection of macaques - modeling the progression to AIDS dementia

Zink¹,

Spelman²,

Robinson³

et al. 1998

J Neurovirol

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AIDS dementia complex affects 15 ± 20% of HIV-infected adults and a greater percentage of HIV-infected children. Whether or not an HIV-infected individual develops neurological disease and how early in infection the clinical signs appear is most likely the net result of both viral virulence factors and host factors. Important viral factors include cell tropism and sequences that determine neurovirulence. The host factors include the cellular expression of viral co-receptors and maintenance of competent immune responses. The pathogenesis of AIDS dementia complex is dif®cult to study in the human host because of the dif®culty in identifying acutely infected individuals and the inaccessibility of human brain tissue for examination during infection. The SIV/ macaque model is excellent for the study of viral virulence factors and host responses to infection. This review outlines how the SIV/macaque model has been used to identify viral factors that are important for the development of neurological disease, to determine when HIV enters the brain, and to characterize the host immune responses affecting virus entry to the CNS and the development of neurological disease.

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Relationship of human immunodeficiency virus type 1 sequence heterogeneity to stage of disease.

Cited by 205 publications

References 53 publications

Cell-Free Human Immunodeficiency Virus Type 1 Transcytosis through Primary Genital Epithelial Cells

Cell-Free Human Immunodeficiency Virus Type 1 Transcytosis through Primary Genital Epithelial Cells

Genetic drift and within-host metapopulation dynamics of HIV-1 infection

SIV infection of macaques - modeling the progression to AIDS dementia

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