Longitudinal Analysis of Quantitative Virologic Measures in Human Immunodeficiency Virus-Infected Subjects with &gt;=400 CD4 Lymphocytes: Implications for Applying Measurements to Individual Patients

Paxton, William B.; Coombs, Robert W.; McElrath, M. Juliana; Keefer, Michael C.; Sinangil, Faruk; Chernoff, David; Demeter, Lisa M.; Williams, Bruce; Corey, Lawrence

doi:10.1093/infdis/175.2.247

Cited by 94 publications

(74 citation statements)

References 25 publications

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“…A medical history, physical examination, complete blood cell count, T-cell subset analysis, and HIV-1 testing were done at the screening visit to confirm eligibility. HIV-1 infection was excluded by the following tests done at the screening visit and study day 0: HIV-1/2 enzyme-linked immunosorbent assay (ELISA) and Western blot (50), HIV-1 plasma RNA reverse transcription-PCR (Amplicor HIV-1 Monitor; Roche Molecular Systems) (19), and peripheral blood mononuclear cell (PBMC) DNA PCR (41). HIV-1/2 ELISA and Western blot were repeated every 3 months, and HIV-1 PBMC DNA PCR was performed again 4 weeks and 8 weeks after enrollment and then repeated yearly.…”

Section: Methodsmentioning

confidence: 99%

Combined Effect of CCR5-Δ32 Heterozygosity and the CCR5 Promoter Polymorphism −2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission

Hladik

Liu²,

Speelmon

et al. 2005

J Virol

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Exposed seronegative individuals (ES) with persistent high-risk sexual behavior may be less susceptible to human immunodeficiency virus type 1 (HIV-1) infection because they carry the chemokine receptor (CR) gene alleles CCR5 open reading frame (ORF) ⌬32, CCR5 promoter ؊2459G, or CCR2 ORF 64I (CCR2-64I), all of which have been found to diminish HIV-1 infectivity and/or disease progression. To investigate this, we determined the haplotypes for these three genetic loci in 93 ES and 247 low-risk control individuals. To test if protective haplotypes exert their effect by modulating CR expression, we measured the protein expression of CCR5 and CXCR4 on circulating CD4؉ T cells and CD14 ؉ monocytes in 71 ES and 92 controls. To avoid investigator bias, the analysis was performed without knowledge of each subject's risk and genotype. The CCR5 ؊2459G allele was significantly enriched in ES Caucasian men, who constituted the majority (84%) of the ES cohort, compared to the control Caucasian men (P ‫؍‬ 0.02). This increase was mostly attributable to a higher frequency of the ؊2459 A/G versus the ؊2459 A/A genotype in individuals heterozygous for the ⌬32 allele (P ‫؍‬ 0.012). No protective influence of the CCR2-64I allele was observed. The haplotypes CCR5 ORF ⌬32/CCR5 ؊2459A (in complete linkage disequilibrium) and CCR5 ORF wt/CCR5 ؊2459G had a cumulative negative effect on the expression of CCR5, since we measured significantly reduced CCR5 densities on both T-helper cells and monocytes only when both haplotypes were present. Densities of CCR5 on lymphocytes and monocytes were correlated (r ‫؍‬ 0.59; P < 0.0001), indicating concordance of CCR5 expression patterns across different cell types. We conclude that the CCR5 ORF ⌬32/wt-CCR5 ؊2459 A/G genotype combination offers an advantage in resisting sexual HIV-1 transmission and that this effect is mediated by a relative paucity of CCR5 on potential target cells of HIV-1.

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Section: Methodsmentioning

confidence: 99%

Combined Effect of CCR5-Δ32 Heterozygosity and the CCR5 Promoter Polymorphism −2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission

Hladik

Liu²,

Speelmon

et al. 2005

J Virol

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“…A medical history, physical examination, complete blood cell count, T cell subset analysis, and HIV-1 testing were performed at the screening visit to confirm eligibility. HIV-1 infection was excluded by the following tests performed at the screening visit and on study day 0: HIV-1/2 ELISA and Western blot (37), HIV-1 plasma RNA RT-PCR (Amplicor HIV-1 Monitor; Roche, Branchburg, NJ) (38), and PBMC DNA PCR (39). HIV-1/2 ELISA and Western blot were repeated every 3 mo.…”

Section: Study Populationmentioning

confidence: 99%

Most Highly Exposed Seronegative Men Lack HIV-1-Specific, IFN-γ-Secreting T Cells

Hladik¹,

Desbien²,

Lang³

et al. 2003

The Journal of Immunology

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Naturally acquired cellular immunity in individuals who have been exposed to HIV-1 but have remained uninfected may hold clues for the design of an effective HIV vaccine. To determine the presence and nature of such an HIV-1-specific immune response, we evaluated the quantity and fine specificity of HIV-1-reactive IFN-γ-secreting T cells in a group of highly exposed seronegative men having sex with men. All 46 ES reported frequent unprotected anal sex with known HIV-1-infected partners at enrollment, and high risk activities continued in at least one-half of the volunteers for up to >6 years of observation. Despite the high frequency of unprotected anal intercourse and potential HIV-1 exposure, the vast majority of individuals demonstrated no or very low numbers of HIV-1-specific, IFN-γ-secreting T cells. Even when HIV-1 epitopes were presented by peptide-pulsed autologous dendritic cells in 15 of the highest risk volunteers, HIV-1-specific T cells remained infrequent, and the proportion of responders was not significantly different from that in a lower risk seronegative control cohort. Only PBMC from two individuals who have remained uninfected to date exhibited distinctly positive responses. However, these responses rarely persisted over time, single epitope specificities were identified in only one volunteer, and HIV-1-specific memory T cell clones did not expand in vitro. HIV-1-specific, IFN-γ-secreting T cells are thus unlikely to substantially contribute to resistance against infection in most exposed seronegative men having sex with men.

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“…Nearly half of the HIV-2-infected individuals have a nearly quiescent infection, and the paired levels of viral RNA and proviral DNA differ dramatically from those found in HIV-1 infection, where RNA-to-DNA ratios are only rarely less than 1.0 and are above 10.0 in the majority of individuals (4,27,34). It is not known if these represent infections that are truly latent at the molecular level; we have been able to detect viral RNA in some individuals with less than 100 copies/ml by a qualitative RT-PCR (S. Popper, unpublished data), suggesting that virus may be produced at very low levels and that the proviruses present in these individuals are not defective.…”

mentioning

confidence: 99%

Low Plasma Human Immunodeficiency Virus Type 2 Viral Load Is Independent of Proviral Load: Low Virus Production In Vivo

Popper¹,

Sarr²,

Guèye-Ndiaye

et al. 2000

J Virol

128

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Levels of virus in the plasma are closely related to the pathogenicity of human immunodeficiency virus type 1 (HIV-1). HIV-2 is much less pathogenic than HIV-1, and infection with HIV-2 leads to significantly lower plasma viral load. To identify the source of this difference, we measured both viral RNA and proviral DNA in matched samples from 34 HIV-2-infected individuals. Nearly half had undetectable viral RNA loads (<100 copies/ml), but levels of proviral DNA were relatively high and confirmed that quantities of provirus in HIV-1 and HIV-2 infection were similar. Overall, HIV-2 proviral DNA load did not correlate with viral RNA load, and higher viral RNA load was associated with increased production of plasma virus from the proviral template. These results suggest that low viral load in HIV-2 infection is due to decreased rates of viral production, rather than differences in target cell infectivity.

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Longitudinal Analysis of Quantitative Virologic Measures in Human Immunodeficiency Virus-Infected Subjects with >=400 CD4 Lymphocytes: Implications for Applying Measurements to Individual Patients

Cited by 94 publications

References 25 publications

Combined Effect of CCR5-Δ32 Heterozygosity and the CCR5 Promoter Polymorphism −2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission

Combined Effect of CCR5-Δ32 Heterozygosity and the CCR5 Promoter Polymorphism −2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission

Most Highly Exposed Seronegative Men Lack HIV-1-Specific, IFN-γ-Secreting T Cells

Low Plasma Human Immunodeficiency Virus Type 2 Viral Load Is Independent of Proviral Load: Low Virus Production In Vivo

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