HIV-1-Specific Enzyme-Linked Immunosorbent Spot Assay Responses in HIV-1-Exposed Uninfected Partners in Discordant Relationships Compared to Those in Low-Risk Controls

Guthrie, Brandon L.; Lohman-Payne, Barbara; Liu, Amy; Bosire, Rose; Nuvor, Samuel Victor; Choi, Robert Y.; Mackelprang, Romel D.; Kiarie, James; Rosa, Stephen C. De; Richardson, Barbra A.; John‐Stewart, Grace; Farquhar, Carey

doi:10.1128/cvi.00179-12

Cited by 11 publications

(13 citation statements)

References 51 publications

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“…Conversely, positive responses in ESNs were infrequent (in 2 out of 6 subjects) and of very low magnitude. This result is in line with several reports indicating that detection of HIV-specific cellular immune responses in PBMCs from ESN can only be evidenced after cultured, expanded or boosted protocols and, still, subjects with positive responses are the less abundant ( Ruiz-Riol et al, 2015 , Guardo et al, 2015 , Ritchie et al, 2011 , Addo et al, 2011 , Guthrie et al, 2012 , Pala et al, 2013 , Nguyen et al, 2006 , Alimonti et al, 2006 ). Then, the interpretation of those positive responses should be done with caution.…”

Section: Discussionsupporting

confidence: 92%

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

et al. 2017

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As the HIV/AIDS pandemic still progresses, understanding the mechanisms governing viral transmission as well as protection from HIV acquisition is fundamental. In this context, cohorts of HIV serodiscordant heterosexual couples (SDC) represent a unique tool. The present study was aimed to evaluate specific parameters of innate, cellular and humoral immune responses in SDC. Specifically, plasma levels of cytokines and chemokines, HIV-specific T-cell responses, gp120-specific IgG and IgA antibodies, and HIV-specific antibody-dependent cellular cytotoxicity (ADCC) activity were assessed in nine HIV-exposed seronegative individuals (ESN) and their corresponding HIV seropositive partners (HIV+-P), in eighteen chronically infected HIV subjects (C), nine chronically infected subjects known to be HIV transmitters (CT) and ten healthy HIV− donors (HD). Very low magnitude HIV-specific cellular responses were found in two out of six ESN. Interestingly, HIV+-P had the highest ADCC magnitude, the lowest IgA levels and the highest IgG/IgA ratio, all compared to CT. Positive correlations between CD4+ T-cell counts and both IgG/IgA ratios and %ADCC killing uniquely distinguished HIV+-P. Additionally, evidence of IgA interference with ADCC responses from HIV+-P and CT is provided. These data suggest for the first time a potential role of ADCC and/or gp120-specific IgG/IgA balance in modulating heterosexual transmission. In sum, this study provides key information to understand the host factors that influence viral transmission, which should be considered in both the development of prophylactic vaccines and novel immunotherapies for HIV-1 infection.

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Section: Discussionsupporting

confidence: 92%

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

et al. 2017

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“…The results from adjusted models suggest activated T cells are hyper‐responsive, secreting higher levels of cytokines when stimulated, and thereby producing false positive ELISpot responses mediated through higher background responses. While these findings support the idea that activated cells may have contributed to false positive HIV‐1‐specific cellular responses through background response, it does not preclude the possibility of the participants being unwilling to acknowledge exposure to HIV‐1 from outside partnerships, exposure that can lead to HIV‐1 specific responses .…”

Section: Discussionmentioning

confidence: 59%

High background in ELISpot assays is associated with elevated levels of immune activation in HIV‐1‐seronegative individuals in Nairobi

Liu

Rosa

Guthrie

et al. 2018

Immunity Inflam & Disease

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IntroductionSpontaneous interferon‐γ (IFNγ) released detected by enzyme‐linked immunospot (ELISpot) assays may be a biological phenomenon. Markers of immune activation levels were assessed as correlates of high background among individuals in Kenya.MethodsCouples concordantly seronegative for HIV‐1 were enrolled. IFN‐γ ELISpot assays were conducted and negative control wells were categorized as having either high or low background (≥50 and <50 SFU/106 peripheral blood mononuclear cells [PBMC], respectively). PBMC were stained for CD4, CD8, and immune activation markers (CD38 and HLA‐DR) and analyzed using flow cytometry. Proportions of activated T‐cells were compared between those with low and high background by Mann–Whitney U test. Correlates of background SFU and immune activation were assessed using regression models.ResultsAmong 58 individuals, 14 (24%) had high background. Frequencies of CD4+CD38+HLA‐DR+ and CD8+CD38+HLA‐DR+ cells were higher in individuals with high background compared to those with low background (P = 0.02). Higher background SFU was associated with history of sexually transmitted infections (P = 0.03), and illness in the past 3 months (P = 0.005), in addition to increased levels of activated CD4+ and CD8+ cells (P range = 0.008–0.03). Female gender and male circumcision decreased levels of CD4+ and CD8+ immune activation (P range = 0.002–0.03). Additionally, higher background SFU and activated CD4+ and CD8+ cells were individually associated with positive ELISpot responses to HIV‐1 peptide pools (P range = 0.01–0.03).ConclusionsThese findings suggest that increased basal immune responses may be a biological mechanism contributing to higher background ELISpot SFU. Systematic exclusion of data from individuals with increased background in IFN‐γ release assays may bias results in population‐based studies.

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“…Finally, we were unable to directly assess the effect of innate peptide levels on HIV-1 risk due to the very low rate of HIV-1 transmission in this cohort. 22 …”

Section: Discussionmentioning

confidence: 99%

“…The women in this study were drawn from a parent cohort described elsewhere. 22 Briefly, eligible participants were ≥18 years of age, reported sexual intercourse with their study partner at least three times in the 3 months prior to screening and planned to remain together for the duration of the study (up to 24 months). We excluded couples that were enrolled in another HIV-1 treatment or prevention trial, or planned to be away from Nairobi for 2 consecutive months during follow-up.…”

Section: Methodsmentioning

confidence: 99%

Depot Medroxyprogesterone Acetate Use Is Associated With Elevated Innate Immune Effector Molecules in Cervicovaginal Secretions of HIV-1–Uninfected Women

Guthrie

Introini

Roxby

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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OBJECTIVE The effects of sex hormones on the immune defenses of the female genital mucosa and its susceptibility to infections are poorly understood. The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may increase risk of HIV-1 acquisition. We assessed the local concentration in the female genital mucosa of cationic polypeptides with reported antiviral activity in relation to DMPA use. METHODS HIV-1-uninfected women were recruited from among couples testing for HIV in Nairobi, Kenya. Cervicovaginal secretion (CVS) samples were collected and the concentrations of HNP1–3, LL-37, lactoferrin, HBD-2 and SLPI were measured by enzyme-linked immunosorbent assays.. Levels of cationic polypeptides in CVS were compared between women who were not using hormonal contraception and those using DMPA, oral, or implantable contraception. RESULTS Among 228 women, 165 (72%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 6 (3%) used a contraceptive implant. Compared to non-users of hormonal contraception, DMPA users had significantly higher mean levels of HNP1–3 (2.38 vs. 2.04 log10 ng/ml; p=0.024), LL-37 (0.81 vs. 0.40 log10 ng/ml; p=0.027), and lactoferrin (3.03 vs. 2.60 log10 ng/ml; p=0.002), whereas SLPI and HBD-2 were similar. CONCLUSIONS Although all analyzed cationic polypeptides have intrinsic antiviral capacity, their interaction and cumulative effect on female genital mucosa susceptibility to infections in vivo has yet to be unraveled. This study suggests a potential mechanism underlying the effect of DMPA on the innate immune defenses, providing a rationale to investigate its effect on HIV-1 acquisition risk.

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HIV-1-Specific Enzyme-Linked Immunosorbent Spot Assay Responses in HIV-1-Exposed Uninfected Partners in Discordant Relationships Compared to Those in Low-Risk Controls

Cited by 11 publications

References 51 publications

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

High background in ELISpot assays is associated with elevated levels of immune activation in HIV‐1‐seronegative individuals in Nairobi

Depot Medroxyprogesterone Acetate Use Is Associated With Elevated Innate Immune Effector Molecules in Cervicovaginal Secretions of HIV-1–Uninfected Women

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