Broad Human Immunodeficiency Virus (HIV)–Specific T Cell Responses to Conserved HIV Proteins in HIV‐Seronegative Women Highly Exposed to a Single HIV‐Infected Partner

Promadej, Nattawan; Costello, Caroline; Wernett, Mary M; Kulkarni, Prasad S.; Robison, Valerie A.; Nelson, Kenrad E.; Hodge, Thomas; Suriyanon, Vinai; Duerr, Ann; McNicholl, Janet M.

doi:10.1086/368127

Cited by 37 publications

(19 citation statements)

References 53 publications

(51 reference statements)

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“…Interestingly, despite low HIV exposure, a relatively high prevalence of HIV-specific T cells response was seen in this cohort of ESN individuals. Similarly, high prevalence has been found in previous studies using different cohorts of ESN individuals (4,8,26), although this has not always been the case (9). More intriguing was the fact that ESN individuals with infected partners having undetectable plasma viremia exhibited more frequently HIV-specific immune responses than ESN individuals with viremic partners.…”

Section: Discussionsupporting

confidence: 56%

“…Several T cell subsets were significantly increased in ESN S ome individuals remain HIV-seronegative despite repeated unprotected exposures to the virus (1). These exposed but seronegative (ESN) individuals include commercial sex workers (2), men having sex with men (3), injection drug users (4), hemophiliacs who received contaminated blood preparations (5), health care workers with accidental percutaneous exposure to infected blood (6), infants born to HIV-infected mothers (7), and individuals with HIV-infected heterosexual partners (8)(9)(10)(11). The mechanisms of protection from infection in ESN individuals are largely undefined and most likely are multifactorial (1,12).…”

mentioning

confidence: 99%

“…Thus, the interpretation of results in terms of a protective role of immune responses on resistance to HIV infection is often difficult. In contrast, most studies examining ESN individuals with stable sexual HIV-infected partners have selected only couples with an HIV-partner presenting high-level viremia (8,9). In this regard, and given the cross-sectional design of these studies, the demonstration of HIV-specific immune responses cannot be considered as a proof of resistance to infection as it can only reflect exposure to the virus.…”

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confidence: 99%

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Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

Restrepo

Rallón

Romero³

et al. 2010

The Journal of Immunology

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HIV-specific T cells response and T cell activation are frequently seen in exposed seronegative individuals (ESN). In this study, we report HIV-specific response and level of T cell activation in ESN partners of HIV-infected patients presenting low or undetectable levels of HIV-RNA. We evaluated 24 HIV-serodiscordant couples. ESN were classified into three categories of exposure to HIV (very low, low, and moderate-high), considering levels of HIV-RNA in their infected partner and frequency of sexual high-risk practices within the last 12 mo. HIV-specific T cell responses and activation levels in T cell subsets were evaluated by flow cytometry. We reported that 54% of ESN had detectable HIV-specific T cells response, being the highest prevalence seen in the low exposure group (64%). Several T cell subsets were significantly increased in ESN when compared with controls: CD4+CD38+ (p = 0.006), CD4+HLA-DR−CD38+ (p = 0.02), CD4+CD45RA+CD27+HLA-DR−CD38+ (p = 0.002), CD8+CD45RA+CD27+CD38−HLA-DR+ (p = 0.02), and CD8+CD45RA+CD27−CD38+HLA-DR+ (p = 0.03). Activation of CD8+ T cells was increased in ESN with detectable HIV T cell responses compared with ESN lacking these responses (p = 0.04). Taken together, these results suggest that persistent but low sexual HIV exposure is able to induce virus-specific T cells response and immune activation in a high proportion of ESN, suggesting that virus exposure may occur even in conditions of maximal viral suppression in the HIV-infected partner.

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Section: Discussionsupporting

confidence: 56%

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confidence: 99%

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confidence: 99%

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Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

Restrepo

Rallón

Romero³

et al. 2010

The Journal of Immunology

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“…These high-risk seronegative (HRSN) individuals include children born from HIV-infected mothers (1)(2)(3)(4), female sex workers in areas where HIV infection is epidemic (5)(6)(7)(8)(9), hemophiliacs who received HIV-1-contaminated blood preparations (10,11), and sexual partners of HIV-1-infected individuals (12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

“…Heterozygosity for the CCR5-⌬32 allele and high expression levels of the CCR5 ligand RANTES have also been associated with resistance to HIV infection (22)(23)(24). HIV-specific CTLs have been identified in many exposed seronegative individuals, suggesting a role for HIV-specific CTL responses in resistance to HIV-1 infection (5,15,(25)(26)(27)(28)(29)(30). However, these responses do not necessarily reflect protective cellular immunity from infection but may merely reflect exposure to the virus since we found similar amounts and specificity of HIV-specific CTLs in seronegative men who later became HIV-1 seropositive (31,32).…”

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confidence: 99%

Low-Level CD4+ T Cell Activation Is Associated with Low Susceptibility to HIV-1 Infection

Koning

Otto

Hazenberg

et al. 2005

The Journal of Immunology

111

107

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Different features have been associated with low susceptibility to HIV type 1 (HIV-1) infection in exposed seronegative individuals. These include genetic make-up such as homozygosity for the CCR5-Δ32 allele and the presence of HIV-specific CTLs. We studied immune activation and immune responsiveness in relation to HIV-1 susceptibility in 42 high-risk seronegative (HRSN) participants of the Amsterdam Cohort Studies and 54 men from the same cohort who were seronegative at the moment of analysis but later became HIV seropositive. HRSN had higher naive (CD45RO CD27) CD4 and CD8 T cell numbers and lower percentages of activated (HLADR CD38, CD70) CD4 and proliferating (Ki67) CD4 and CD8 T cells, irrespective of previous episodes of sexually transmittable infections. Furthermore, whole blood cultures from HRSN showed lower lymphoproliferative responses than healthy laboratory controls. These data suggest that low levels of immune activation and low T cell responsiveness may contribute to low HIV susceptibility.

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Increased detection of proliferating, polyfunctional, HIV‐1‐specific T cells in DNA‐modified vaccinia virus Ankara‐vaccinated human volunteers by cultured IFN‐γ ELISPOT assay

et al. 2009

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Induction of a long-term immunological memory, which can expand and defend the host upon pathogen encounter, is the ''holy grail'' of vaccinology. Here, using a sensitive cultured IFN-c ELISPOT assay, we show that 50% (15 out of 30) of healthy, HIV-1/2-uninfected volunteers who received pTHr.HIVA DNA prime-modified vaccinia virus Ankara. HIVA boost vaccine regimen 1 to 3 1/2 years ago had detectable HIV-1-specific T-cell responses. These T cells, predominantly of the CD4 1 subtype, could proliferate and produce multiple cytokines in response to in vitro peptide stimulation. Peptide mapping studies showed that the vaccine-induced CD4 1 T cells were mostly directed toward epitopes targeted in HIV-1-infected individuals. In addition, we used the same assay to re-evaluate 51 volunteers from past vaccine trial IAVI-006 and corrected the previously reported 10% of vaccine responders to 50%. Thus, we confirmed that cultured assays are a valuable tool for studying T-cell memory. These results are discussed in the context of the current state-of-affairs of the HIV-1 vaccine field.Key words: Clinical trial . DNA-MVA vaccines . HIV-1 . Memory T cells IntroductionDespite proven methods of prevention and/or decrease of transmission, all efforts to slow the rate of new HIV-1 infections are failing in most countries around the world, including the USA (http://www.unaids.org/). The best solution to control of the HIV-1 epidemic remains the development of a safe, effective and accessible preventive vaccine [1]. The aim of vaccination is induction of long-lived, pathogen-specific circulating antibodies and cellular immunological memory, which together provide a faster and more efficient defense of the host following exposure to the pathogen. A central role in both the T-and B-cell memory development is played by CD4 1 T cells [2,3], the functionality of which is tuned by the non-adaptive innate response [4]. It is the CD4 1 T-cell population that is decimated by HIV-1-infection, which eventually leads to opportunistic infections [5,6].The long-term aim of our effort is development of an effective HIV-1 vaccine. In particular, we explore strategies for eliciting HIV-1-specific T-cell responses, which could on their own, or together with vaccine-induced anti-HIV-1 antibodies, limit tissue damage during HIV-1 infection. Our first vaccine platform was designed as a heterologous DNA prime-modified vaccinia virus Ankara (MVA) boost regimen delivering a common immunogen HIVA, which consists of consensus African clade A Gag p24 and The most sensitive assay employed and validated by the IAVI-016 trial was the IFN-g ELISPOT assay combined with a prior 10-day-culture expansion of PBMC using immunogen-derived peptides and externally supplemented cytokines. This so called cultured IFN-g ELISPOT assay increased the frequencies of specific T cells more than 24-fold compared with the ex vivo assay and detected vaccine-induced HIV-1-specific responses in all (8 out of 8) IAVI-016 subjects who received the pTHr.HIVA DNA-MVA.HIVA regimen [14]. Thes...

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Broad Human Immunodeficiency Virus (HIV)–Specific T Cell Responses to Conserved HIV Proteins in HIV‐Seronegative Women Highly Exposed to a Single HIV‐Infected Partner

Cited by 37 publications

References 53 publications

Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

Low-Level Exposure to HIV Induces Virus-Specific T Cell Responses and Immune Activation in Exposed HIV-Seronegative Individuals

Low-Level CD4+ T Cell Activation Is Associated with Low Susceptibility to HIV-1 Infection

Increased detection of proliferating, polyfunctional, HIV‐1‐specific T cells in DNA‐modified vaccinia virus Ankara‐vaccinated human volunteers by cultured IFN‐γ ELISPOT assay

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