Human immunodeficiency virus type 1 requires interactions with CD4 and coreceptors for infection. The chemokine receptors, CCR5 and CXCR4 are major coreceptors and all HIV-1 isolates use one or both. CCR5-using (R5) viruses account for almost all transmissions. Preliminary data presented shows that R5 viruses vary considerably in cell tropism depending on their capacity to exploit low levels of CD4 and/or CCR5 for infection. Thus, R5 tropisms can be described as narrow/R5 and broad/R5. Broad/R5 envelopes conferred infection of macrophages and T-cells that expressed low levels of CD4 and/or CCR5, while narrow/R5 envelopes only infected cells with high CD4 levels. Preliminary data also suggests that narrow/R5 envelopes are more resistant to neutralizing antibodies. Of note, envelopes with broad/R5 tropism were identified in immunoprivileged brain tissue. Our hypothesis is that neutralization sensitive, broad/R5 viruses evolve late in disease when immunity declines or in immunoprivileged tissues. Such viruses may preferentially transmit and predominate in acute infection before neutralizing antibodies arise. The origins and phenotypes of HIV-1 in semen are poorly defined. Whether R5 strains that confer broad tropism are present is not known. Several distinct sources may contribute to the pool of virus in semen, including both immune and immunoprivileged tissues e.g. the testes. For some individuals, HIV-1 sequences in semen show distinct lineages from those in blood. The extent HIV-1 sequence variation in semen translates into different biological functions e.g. tropism, that affect capacity of HIV-1 to transmit is unknown. Moreover, several studies of donor/recipient transmission pairs demonstrate that transmission is highly selective where only a small subset of viral genotypes are transmitted. This proposal aims to investigate the biological properties of HIV-1 envelopes present in semen and define the characteristics that facilitate transmission into cervical explant cultures. Importantly, will envelopes that confer transmission be vulnerable to neutralizing antibodies? The following three aims are proposed:
Aim 1. Analysis of cell tropism and receptor requirements of HIV-1 R5 envelopes amplified from semen and blood sampled at different disease stages.
Aim 2. Evaluation of the biological properties of semen and blood derived HIV-1 envelopes including sensitivity to neutralizing antibodies, receptor ligands and envelope interactions with CD4 and CCR5.
Aim 3. Assessment of semen envelopes for their capacity to confer infection of cervical explant cultures.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD049273-05
Application #
7616164
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Shirazi, Yasaman
Project Start
2005-07-15
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$253,372
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Duenas-Decamp, Maria Jose; Peters, Paul; Burton, Dennis et al. (2008) Natural resistance of human immunodeficiency virus type 1 to the CD4bs antibody b12 conferred by a glycan and an arginine residue close to the CD4 binding loop. J Virol 82:5807-14
Peters, Paul J; Duenas-Decamp, Maria J; Sullivan, W Matthew et al. (2008) Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors. Retrovirology 5:5
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