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      Upregulation of PTPRC and Interferon Response Pathways in HIV-1 Seroconverters Prior to Infection

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          Abstract

          Human immunodeficiency virus 1 (HIV-1) exposed seronegative (HESN) individuals may have unique characteristics that alter susceptibility to HIV-1 infection. However, identifying truly exposed HESN is challenging. We utilized stored data and biospecimens from HIV-1 serodifferent couple cohorts, in which couples’ HIV-1 exposures were quantified based on unprotected sex frequency and viral load of the partner with HIV-1. We compared peripheral blood gene expression between 15 HESN and 18 seroconverters prior to infection. We found PTPRC (encoding CD45 antigen) and interferon-response pathways had significantly higher expression among individuals who went on to become seropositive and thus may be a signature for increased acquisition risk.

          Abstract

          We analyzed transcriptional signatures associated with HIV acquisition in an African cohort with quantified HIV exposure. PTPRC (CD45 antigen) and interferon-response pathways, both markers of immune activation, had significantly higher expression among individuals who went on to acquire HIV.

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          Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

          Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.) 2010 Massachusetts Medical Society
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            Genomewide Association Study for Determinants of HIV-1 Acquisition and Viral Set Point in HIV-1 Serodiscordant Couples with Quantified Virus Exposure

            Background Host genetic factors may be important determinants of HIV-1 sexual acquisition. We performed a genome-wide association study (GWAS) for host genetic variants modifying HIV-1 acquisition and viral control in the context of a cohort of African HIV-1 serodiscordant heterosexual couples. To minimize misclassification of HIV-1 risk, we quantified HIV-1 exposure, using data including plasma HIV-1 concentrations, gender, and condom use. Methods We matched couples without HIV-1 seroconversion to those with seroconversion by quantified HIV-1 exposure risk. Logistic regression of single nucleotide polymorphisms (SNPs) for 798 samples from 496 HIV-1 infected and 302 HIV-1 exposed, uninfected individuals was performed to identify factors associated with HIV-1 acquisition. In addition, a linear regression analysis was performed using SNP data from a subset (n = 403) of HIV-1 infected individuals to identify factors predicting plasma HIV-1 concentrations. Results After correcting for multiple comparisons, no SNPs were significantly associated with HIV-1 infection status or plasma HIV-1 concentrations. Conclusion This GWAS controlling for HIV-1 exposure did not identify common host genotypes influencing HIV-1 acquisition. Alternative strategies, such as large-scale sequencing to identify low frequency variation, should be considered for identifying novel host genetic predictors of HIV-1 acquisition.
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              Immune Quiescence: a model of protection against HIV infection

              Aberrant immune activation is a strong correlate of HIV disease progression, but little is known about how immune activation alters susceptibility to HIV infection. Susceptibility to HIV infection varies between individuals, but the immunological determinants of HIV transmission are not well understood. Here, we present evidence from studies of HIV transmission in the context of clinical trials and HIV-exposed seronegative (HESN) cohorts that implicates elevated immune activation as a risk factor for acquiring HIV. We propose a model of protection from infection based on a phenotype of low baseline immune activation referred to as immune quiescence. Immune quiescence is evidenced by reduced expression of T cell activation markers, low levels of generalized gene transcription and low levels of proinflammatory cytokine and chemokine production in the periphery and genital mucosa of HESN. Since HIV preferentially replicates in activated CD4+ T cells, immune quiescence may protect against infection by limiting HIV target cell availability. Although the determinants of immune quiescence are unclear, several potential factors have been identified that may be involved in driving this phenotype. HESN were shown to have elevated proportions of regulatory T cells (Tregs), which are known to suppress T cell activation. Likewise, proteins involved in controlling inflammation in the genital tract have been found to be elevated in HESN. Furthermore, expression of interferon regulatory factor 1 (IRF-1) is reduced in HESN as a consequence of genetic polymorphisms and differential epigenetic regulation. Since IRF-1 is an important regulator of immune responses, it may play a role in maintaining immune quiescence. Based on this model, we propose a novel avenue for HIV prevention targeted based on reducing host mucosal immune activation.
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                Author and article information

                Contributors
                Journal
                J Infect Dis
                J Infect Dis
                jid
                The Journal of Infectious Diseases
                Oxford University Press
                0022-1899
                1537-6613
                01 March 2023
                13 January 2023
                13 January 2023
                : 227
                : 5
                : 714-719
                Affiliations
                Institute for Public Health Genetics, University of Washington , Seattle, Washington, USA
                Canadian Centre for Computational Genomics-Montréal Node , Montreal, Quebec, Canada
                School of Public Health, Makerere University , Kampala, Uganda
                Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Canada
                Perinatal HIV Research Unit, University of the Witwatersrand , Johannesburg, South Africa
                Perinatal HIV Research Unit, University of the Witwatersrand , Johannesburg, South Africa
                Department of Obstetrics and Gynecology, University of Nairobi , Nairobi, Kenya
                Department of Global Health, University of Washington , Seattle, Washington, USA
                Department of Global Health, University of Washington , Seattle, Washington, USA
                Department of Medicine, University of Washington , Seattle, Washington, USA
                Department of Epidemiology, University of Washington , Seattle, Washington, USA
                Department of Population and Quantitative Health Science, Case Western Reserve University , Cleveland, Ohio, USA
                Department of Global Health, University of Washington , Seattle, Washington, USA
                Department of Medicine, University of Washington , Seattle, Washington, USA
                Department of Pediatrics, University of Washington , Seattle, Washington, USA
                Department of Global Health, University of Washington , Seattle, Washington, USA
                Department of Obstetrics and Gynecology, University of Washington , Seattle, Washington, USA
                Author notes

                M. J. C., J. R. L., and R. D. M contributed equally.

                Correspondence: R. D. Mackelprang, PhD, Department Obstetrics and Gynecology, University of Washington, 1959 NE Pacific Street, Box 356460, Seattle, WA 98195 ( romelm@ 123456uw.edu ); and
                J. R. Lingappa, MD, PhD, Department of Global Health, University of Washington, 325 Ninth Avenue, Box 359927, Seattle, WA 98195 ( lingappa@ 123456uw.edu ).

                Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

                Author information
                https://orcid.org/0000-0002-8887-9691
                Article
                jiac498
                10.1093/infdis/jiac498
                9978315
                36637125
                4b987d3d-6297-40e4-a01d-a2ea0f23e4d3
                © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 02 June 2022
                : 22 December 2022
                : 02 February 2023
                Page count
                Pages: 6
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases, doi 10.13039/100000060;
                Funded by: National Institutes of Health, doi 10.13039/100000002;
                Award ID: 5R21AI087427-02
                Award ID: 5R01AI134293-03
                Categories
                Brief Report
                HIV/Aids
                AcademicSubjects/MED00290

                Infectious disease & Microbiology
                host resistance,hiv-1,acquisition,gene expression,microarray
                Infectious disease & Microbiology
                host resistance, hiv-1, acquisition, gene expression, microarray

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