The ‘immunologic advantage’ of HIV-exposed seronegative individuals

Miyazawa, Masaaki; Lopalco, Lucia; Mazzotta, Francesco; Caputo, Sergio Lo; Veas, Francisco; Clerici, Mario

doi:10.1097/qad.0b013e3283196a80

Cited by 104 publications

(87 citation statements)

References 154 publications

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“…A systematic review of these studies suggests that natural resistance to HIV infection in highly exposed individuals is mediated by multiple mechanisms, conferring on them an ''immunologic advantage'' that may be related to innate and/or adaptive immune systems. 66,67 Although offering only a partial explanation to the natural resistance to HIV infection, 68 observations in female sex workers in Nairobi with frequent HIV exposure, [69][70][71] in exposed uninfected infants with strong HIV-1-specific T cell responses, 72 and more recently in discordant couples 73 suggest that recurrent viral exposure may lead to priming of HIV-specific systemic and mucosal immune responses. These findings suggest that persons receiving PrEP who are exposed to HIV may generate HIV-specific T cell responses, potentially contributing to protection against the establishment of HIV infection.…”

Section: Mucosal Exposure In the Absence Of Chronic Infection Can Indmentioning

confidence: 99%

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

Excler

Rida²,

Priddy

et al. 2011

AIDS Research and Human Retroviruses

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While the long-term goal is to develop highly effective AIDS vaccines, first generation vaccines may be only partially effective. Other HIV prevention modalities such as preexposure prophylaxis with antiretrovirals (PrEP) may have limited efficacy as well. The combined administration of vaccine and PrEP (VAXPREP), however, may have a synergistic effect leading to an overall benefit that is greater than the sum of the individual effects. We propose two test-of-concept trial designs for an AIDS vaccine plus oral or topical ARV. In one design, evidence that PrEP reduces the risk of HIV acquisition is assumed to justify offering it to all participants. A two-arm study comparing PrEP alone to VAXPREP is proposed in which 30 to 60 incident infections are observed to assess the additional benefit of vaccination on risk of infection and setpoint viral load. The demonstrated superiority of VAXPREP does not imply vaccine alone is efficacious. Similarly, the lack of superiority does not imply vaccine alone is ineffective, as antagonism could exist between vaccine and PrEP. In the other design, PrEP is assumed not to be in general use. A 2Â2 factorial design is proposed in which high-risk individuals are randomized to one of four arms: placebo vaccine given with placebo PrEP, placebo vaccine given with PrEP, vaccine given with placebo PrEP, or VAXPREP. Between 60 and 210 infections are required to detect a benefit of vaccination with or without PrEP on risk of HIV acquisition or setpoint viral load, with fewer infections needed when synergy is present.

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Section: Mucosal Exposure In the Absence Of Chronic Infection Can Indmentioning

confidence: 99%

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

Excler

Rida²,

Priddy

et al. 2011

AIDS Research and Human Retroviruses

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“…The notion that a subset of human subjects remains uninfected despite multiple exposures to HIV-1 has been known for years (8,9). Natural resistance to HIV-1 *Scientific Institute for Recovery and Care E. Medea, 23842 Bosisio Parini, Italy; is thought to result from a favorable genetic and immunologic milieu that generates systemic and mucosal cell-mediated immune responses (10)(11)(12)(13). In this study, we analyzed the role of the TLR3 Leu412Phe variant in HIV-1 infection.…”

mentioning

confidence: 99%

A Common Polymorphism in TLR3 Confers Natural Resistance to HIV-1 Infection

Sironi

Biasin

Cagliani

et al. 2012

The Journal of Immunology

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106

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TLR3 recognizes dsRNA and activates antiviral immune responses through the production of inflammatory cytokines and type I IFNs. Genetic association studies have provided evidence concerning the role of a polymorphism in TLR3 (rs3775291, Leu412Phe) in viral infection susceptibility. We genotyped rs3775291 in a population of Spanish HIV-1–exposed seronegative (HESN) individuals who remain HIV seronegative despite repeated exposure through i.v. injection drug use (IDU-HESN individuals) as witnessed by their hepatitis C virus seropositivity. The frequency of individuals carrying at least one 412Phe allele was significantly higher in IDU-HESN individuals compared with that of a matched control sample (odds ratio for a dominant model = 1.87; 95% confidence interval, 1.06–3.34; p = 0.023). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Similar results were obtained: the frequency of individuals carrying at least one 412Phe allele was significantly higher compared with that of a matched control sample (odds ratio, 1.79; 95% confidence interval, 1.05–3.08; p = 0.029). In vitro infection assays showed that in PBMCs carrying the 412Phe allele, HIV-1Ba-L replication was significantly reduced (p = 0.025) compared with that of Leu/Leu homozygous samples and was associated with a higher expression of factors suggestive of a state of immune activation (IL-6, CCL3, CD69). Similarly, stimulation of PBMCs with a TLR3 agonist indicated that the presence of the 412Phe allele results in a significantly increased expression of CD69 and higher production of proinflammatory cytokines including IL-6 and CCL3. The data of this study indicate that a common TLR3 allele confers immunologically mediated protection from HIV-1 and suggest the potential use of TLR3 triggering in HIV-1 immunotherapy.

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“…An immunologically interesting group includes serodiscordant couples and commercial sex workers who do not become infected with HIV despite extensive exposure. 23 These highly-exposed seronegative individuals appear to be in a state of HIVspecific immune activation, and several authors have described HIV-specific CD4 + T lymphocytes as potential immunological correlates of protection from persistent infection. [24][25][26] These phenomena indicate that HIV-specific CD4 + T cell responses can be induced or augmented by exposure to HIV without infection.…”

Section: 5mentioning

confidence: 99%