HIV Dynamics in Seminal Plasma during Primary HIV Infection

Stekler, Joanne D.; Sycks, Brian J.; Holte, Sarah; Maenza, Janine; Stevens, Claire E.; Dragavon, Joan; Collier, Ann C.; Coombs, Robert W.

doi:10.1089/aid.2008.0014

Cited by 40 publications

(39 citation statements)

References 49 publications

(57 reference statements)

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“…In contrast, previous rhesus macaque challenge models with cell-free SIV used very high viral doses (10 6 to 10 7 viral RNA copies/inoculum) (9,29,30) in order to initiate infection. Such a high cell-free viral burden has been reported in only 3 of 89 HIV-1-infected patients (31) and is much higher than the typical cell-free viral burden in the semen of infected individuals (maximum, 4 ϫ 10 5 viral RNA copies/ml) (20). The superior infectivity of cell-associated HIV-1/SIV versus cell-free HIV-1/SIV in a mucosal infection through the colon (ex vivo and in vivo) may not be limited to colon infection, as recent publications indicate that cellassociated SIV can also initiate efficient infection through the intact vaginal mucosa in an in vivo macaque monkey model (14).…”

Section: Discussionmentioning

confidence: 97%

Efficiency of Cell-Free and Cell-Associated Virus in Mucosal Transmission of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

Kolodkin-Gal

Hulot

Korioth-Schmitz

et al. 2013

J Virol

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Effective strategies are needed to block mucosal transmission of human immunodeficiency virus type 1 (HIV-1). Here, we address a crucial question in HIV-1 pathogenesis: whether infected donor mononuclear cells or cell-free virus plays the more important role in initiating mucosal infection by HIV-1. This distinction is critical, as effective strategies for blocking cell-free and cell-associated virus transmission may be different. We describe a novel ex vivo model system that utilizes sealed human colonic mucosa explants and demonstrate in both the ex vivo model and in vivo using the rectal challenge model in rhesus monkeys that HIV-1-infected lymphocytes can transmit infection across the mucosa more efficiently than cell-free virus. These findings may have significant implications for our understanding of the pathogenesis of mucosal transmission of HIV-1 and for the development of strategies to prevent HIV-1 transmission. N ovel microbicide and vaccine candidates for human immunodeficiency virus type 1 (HIV-1) are being evaluated preclinically for efficacy by assessing their ability to protect nonhuman primates against cell-free simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) challenges. However, it remains unclear whether cell-associated virus (virus-infected donor mononuclear cells), cell-free virus, or both play the most important roles in initiating mucosal infection by HIV-1 (1-5). This distinction is critical, since effective strategies for blocking cell-free and cell-associated virus transmission may be very different (3, 6, 7). We sought to explore early events in mucosal transmission of HIV-1 and SIV by evaluating the relative efficiency of cell-associated and cell-free virus in initiating mucosal infection. To model these infection events, we developed a novel three-dimensional sealed human colonic mucosa explant system. We utilized this system in association with the SIV distal colon in vivo challenge model in rhesus macaques to evaluate the relative efficiency of initiating mucosal infection using cell-associated virus compared to that of initiating mucosal infection using cell-free virus in vivo. MATERIALS AND METHODS Viruses.A replication-competent CC chemokine receptor type 5 (CCR5)-tropic HIV-1 strain expressing green fluorescence protein (GFP) [HIV-1(R5) NL4.3-BaL-GFP] (8) was utilized for human organ infections, and SIVmac251 (9) was utilized for rhesus monkey tissue infections.TCID 50 for cell-associated virus and cell-free virus. The 50% tissue culture infective dose (TCID 50 ) was determined as previously described (10). Briefly, 4 replicates each of cell-associated virus (starting with 200,000 cells/well) and cell-free virus (starting with concentrated virus) were added to the first column of a 96-well plate. Then, 5-fold dilutions were performed for a total of 9 serial dilutions (1:5 to 1:5 9 ). An additional column with no virus or cells added served as a negative control to measure the background. TZM-bl cells (NIH AIDS Research and Reference Reagent Pr...

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Section: Discussionmentioning

confidence: 97%

Efficiency of Cell-Free and Cell-Associated Virus in Mucosal Transmission of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

Kolodkin-Gal

Hulot

Korioth-Schmitz

et al. 2013

J Virol

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“…Thirty HIV-infected participants in the Seattle LongTerm Non-Progressor (34), Natural Progression, Primary Infection (35)(36)(37), and NIAID/NIH (38) cohorts were selected for this study. HIV controllers (n ϭ 15) were defined by viral loads Ͻ 2,000 RNA copies/ml and CD4 ϩ T-cell counts Ͼ 500.…”

Section: Methodsmentioning

confidence: 99%

Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication

Sunshine

Kim

Carlson

et al. 2014

J Virol

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A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-␥/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P ‫؍‬ 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P ‫؍‬ 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r ‫؍‬ 0.62, P ‫؍‬ 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r ‫؍‬ ؊0.38, P ‫؍‬ 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r ‫؍‬ 0.50, P ‫؍‬ 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.

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“…HIV-associated neurologic disease is relatively common, resulting in significant cognitive and neurologic impairment, but the etiology is incompletely understood (Resnick et al, 1988;Sacktor, 2002;McArthur, 2004;Valcour et al, 2012). The male genital tract has also shown poor ARV penetration (Kashuba et al, 1999;Avery et al, 2011) and is a compartment of concern in that it is the primary site of transmission through HIV-laden semen (Resnick et al, 1988;Stekler et al, 2008;UNAIDS, 2009). Although the ability of ARVs to penetrate these compartments is an important aspect of HIV therapy, in many cases a comprehensive understanding of the distribution of these drugs beyond the blood is lacking.…”

Section: Introductionmentioning

confidence: 99%

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

et al. 2012

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Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in the treatment of human immunodeficiency virus (HIV) infection. EFV is extensively metabolized by cytochrome P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma, seminal plasma, and cerebrospinal fluid from subjects on an EFV-based regimen. The 8-hydroxy EFV metabolite was detected in blood plasma, seminal plasma, and cerebrospinal fluid, with median concentrations of 314.5 ng/ml, 358.5 ng/ml, and 3.37 ng/ml, respectively. In contrast, 7-hydroxy and 8,14-hydroxy EFV were only detected in blood plasma and seminal plasma with median concentrations of 8.84 ng/ml and 10.23 ng/ml, and 5.63 ng/ml and 5.43 ng/ml, respectively. Interestingly, protein-free concentrations of metabolites were only detectable in seminal plasma, where a novel dihdyroxylated metabolite of EFV was also detected. This accumulation of protein-free EFV metabolites was demonstrated to be the result of differential protein binding in seminal plasma compared with that of blood plasma. In addition, the oxidative metabolites of EFV did not present with any significant pharmacologic activity toward HIV-1 as measured using an HIV green fluorescent protein single-round infectivity assay. This study is the first to report the physiologic distribution of metabolites of an antiretroviral into biologic compartments that the virus is known to distribute and to examine their anti-HIV activity. These data suggest that the male genital tract may be a novel compartment that should be considered in the evaluation of drug metabolite exposure.

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HIV Dynamics in Seminal Plasma during Primary HIV Infection

Cited by 40 publications

References 49 publications

Efficiency of Cell-Free and Cell-Associated Virus in Mucosal Transmission of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

Efficiency of Cell-Free and Cell-Associated Virus in Mucosal Transmission of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

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