HIV-infected slow progressors (SP) represent a heterogeneous group of subjects who spontaneously control HIV infection without treatment for several years while showing moderate signs of disease progression. Under conditions that remain poorly understood, a subgroup of these subjects experience failure of spontaneous immunological and virological control. Here we determined the frequency of SP subjects who showed loss of HIV control within our Canadian Cohort of HIV+ Slow Progressors and identified the proinflammatory cytokine IL-32 as a robust biomarker for control failure. Plasmatic levels of the proinflammatory isoforms of IL-32 (mainly β and γ) at earlier clinic visits positively correlated with the decline of CD4 T-cell counts, increased viral load, lower CD4/CD8 ratio and levels of inflammatory markers (sCD14 and IL-6) at later clinic visits. We present here a proof-of-concept for the use of IL-32 as a predictive biomarker for disease progression in SP subjects and identify IL-32 as a potential therapeutic target.

Background: Human IL-32 is a polyfunctional cytokine that was initially reported to inhibit HIV-1 infection. However, recent data suggest that IL-32 may enhance HIV-1 replication by activating the HIV-1 primary targets, CD4+ T-cells. Indeed, IL-32 is expressed in multiple isoforms, some of which are proinflammatory, whereas others are anti-inflammatory. Setting and Methods: Here, we aimed to determine the relative expression of IL-32 isoforms and to test their inflammatory nature and potential to induce HIV-1 production in latently infected cells from virologically suppressed HIV-infected individuals. IL-32 and other cytokines were quantified from plasma and supernatant of CD4+ T-cells by ELISA. Transcripts of IL-32 isoforms were quantified by qRT-PCR in peripheral blood mononuclear cells. The impact of recombinant human IL-32 isoforms on HIV-1 transcription was assessed in CD4+ T-cells from HIV-1+cART+ individuals by qRT-PCR. Results: All IL-32 isoforms were significantly upregulated in HIV-1+cART+ compared to HIVneg individuals with IL-32β representing the dominantly expressed isoform, mainly in T-cells and NK-cells. At the functional level, although IL-32γ induced typical proinflammatory cytokines (IL-6 and IFN-γ) in TCR-activated CD4+ T-cells, IL-32α showed an anti-inflammatory profile by inducing IL-10 but not IL-6 or IFN-γ. However, IL-32β showed a dual phenotype by inducing both pro- and anti-inflammatory cytokines. Interestingly, consistent with its highly pro-inflammatory nature, IL-32γ, but not IL-32α or IL-32β, induced HIV-1 production in latently infected CD4+ T-cells isolated from combined antiretroviral therapy–treated individuals. Conclusions: Our data report on the differential expression of IL-32 isoforms and highlight the potential role of IL-32, particularly the γ isoform, in fueling persistent inflammation and transcription of viral reservoir in HIV-1 infection.

Objectives: To measure prevalence and risk factors for cervical infections among a large sample of women consulting for vaginal discharge in west Africa and to evaluate its syndromic management through a two visit algorithm. Methods: In 11 health centres in Bénin, Burkina Faso, Ghana, Guinée, and Mali 726 women who presented with a vaginal discharge without abdominal pain and who denied being a sex worker (SW) were enrolled. Cervical samples were tested for the detection of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) with polymerase chain reaction (PCR) assays. All participants were treated with single dose (2 g) metronidazole and clotrimazole cream for 3 days. They were randomised to be told either to come back on day 7 only if there was no improvement in the discharge (group A), or to come back on day 7 regardless of response to treatment (group B). Results: Overall, the prevalence of NG and CT was only 1.9% (14/726) and 3.2% (23/726) respectively. Risk factors previously recommended by the WHO were not associated with the presence of cervical infection, with the exception of the number of sex partners in the past 3 months. When taken together, these risk factors had a positive predictive value of only 6.4% to identify cervical infections. Prevalence of cervical infection was not higher in women who came back on day 7, regardless of the strategy used. Prevalence of NG/CT was lower in Ghana and Bénin (5/280, 1.8%), where comprehensive interventions for SW have been ongoing for years, than in the three other countries (27/446, 6.1%, p = 0.01). Conclusions: NG and CT infections are uncommon in west African women who consult for vaginal discharge and who are not SW. Syndromic management of vaginal discharge should focus on the proper management of vaginitis. The control of gonococcal and chlamydial infection should be redesigned around interventions focusing on sex workers.

We developed an instrument for HIV/AIDS behavioral surveillance applicable to youth living in urban West Africa. The instrument includes a comprehensive set of constructs borrowed from the sociocognitive theory of planned behavior as well as measures of parental and peer communication An exploratory (n=189) and validation sample (n=342) of young men and women living in Bamako were interviewed. Scale construct validity was assessed via factor analysis and multiple linear regressions and internal consistency was assessed using Cronbach's coefficient. All constructs had high internal consistency, scales' structure was relatively stable, and associations between different components of the questionnaire were in the predicted directions. Gender, sexual experience and education were significantly associated with attitudes and perception of control. Furthermore, attitudes, perceived behavioral control, perceived norms, and peer communication significantly predicted condom use. This questionnaire offers a valid and reliable tool for assessing young people's sexual behavior in an urban West African setting.

Elite controllers (ECs) are a rare subset of HIV-1 slow progressors characterized by prolonged viremia suppression. HLA alleles B27 and B57 promote the cytotoxic T lymphocyte (CTL)-mediated depletion of infected cells in ECs, leading to the emergence of escape mutations in the viral capsid (CA). Whether those mutations modulate CA detection by innate sensors and effectors is poorly known. Here, we investigated the targeting of CA from B27/B57+ individuals by cytosolic antiviral factors Mx2 and TRIM5α. Toward that aim, we constructed chimeric HIV-1 vectors using CA isolated from B27/B57+ or control subjects. HIV-1 vectors containing B27/B57+-specific CA had increased sensitivity to TRIM5α but not to Mx2. Following exposure to those vectors, cells showed increased resistance against both TRIM5α-sensitive and -insensitive HIV-1 strains. Induction of the antiviral state did not require productive infection by the TRIM5α-sensitive virus, as shown using chemically inactivated virions. Depletion experiments revealed that TAK1 and Ubc13 were essential to the TRIM5α-dependent antiviral state. Accordingly, induction of the antiviral state was accompanied by the activation of NF-κB and AP-1 in THP-1 cells. Secretion of IFN-I was involved in the antiviral state in THP-1 cells, as shown using a receptor blocking antibody. This work identifies innate activation pathways that are likely to play a role in the natural resistance to HIV-1 progression in ECs.