Acute HIV Infection Research Articles

Dramatic Shift in the Etiology of Genital Ulcer Disease Among Patients Visiting a Sexually Transmitted Infections Clinic in Lilongwe, Malawi.

Genital ulcer diseases (GUDs) are a common syndrome associated with sexually transmitted infections. Genital ulcer diseases increase the risk of HIV transmission, necessitating appropriate diagnosis and treatment. We provide an updated GUD etiology assessment in Malawi to guide diagnostic development and treatment algorithms. We enrolled patients 18 years or older presenting with GUD at a sexually transmitted infection clinic in Lilongwe, Malawi, between May and October 2021. We purposively sampled by HIV status. Swabs of ulcers were tested for Treponema pallidum, herpes simplex virus (HSV)-1 and HSV-2, Haemophilus ducreyi, and Chlamydia trachomatis using polymerase chain reaction. Blood was collected for syphilis and HSV-2 serologies and acute HIV testing. Participants were treated per Malawi guidelines. Ulcer resolution (size reduced by >50%) was evaluated 14 days later. Fifty participants enrolled (30 without HIV, 2 with acute HIV infection, 18 with HIV seropositivity; 32 men, 18 women). Forty-six (92%) had an etiology identified. Syphilis was more common among those without HIV (22 of 30 [73%]) than participants with HIV (PWH; 8 of 20 [40%]; P = 0.04). Herpes simplex virus was more common among PWH (11 of 20 [55%]) than participants without (2 of 30 [7%]; P = 0.0002). One-fifth (9 of 50 [18%]) had H. ducreyi. Among those who returned for follow-up (n = 45), 9 (20%) had unresolved ulcers; persistent GUD was slightly more common in PWH (6 of 19 [32%]) than participants without (3 of 26 [12%]; P = 0.14). We observed a dramatic increase in syphilis ulcer proportion in a population whose GUDs were previously HSV predominant. Observed differences in etiology and resolution by HIV status could play an important role in the ongoing transmission and treatment evaluation of GUD.

Modeling the impact of different PrEP targeting strategies combined with a clinic-based HIV-1 nucleic acid testing intervention in Kenya

BackgroundUp to 69% of adults who acquire HIV in Kenya seek care for acute retroviral symptoms, providing an important opportunity for early diagnosis and HIV care engagement. The Tambua Mapema Plus (TMP) trial tested a combined HIV-1 nucleic acid testing, linkage, treatment, and partner notification intervention for adults with symptoms of acute HIV infection presenting to health facilities in coastal Kenya. We estimated the potential impact on the Kenyan HIV epidemic of providing PrEP to individuals testing negative in TMP, if scaled up. MethodsWe developed an agent-based simulation of HIV-1 transmission using TMP data and current Kenyan statistics. PrEP interventions were layered onto a model of TMP as standard of care, to estimate additional potential population-level impact of enrolling HIV-negative individuals identified through TMP on PrEP over 10 years. Four scenarios were modeled: PrEP for uninfected individuals in disclosed serodiscordant couples; PrEP for individuals with concurrent partnerships; PrEP for all uninfected individuals identified through TMP; and PrEP integrated into the enhanced partner services component of TMP. FindingsProviding PrEP to both individuals with concurrent partnerships and uninfected partners identified through enhanced partner services reduced new HIV infections and was efficient based on numbers needed to treat (NNT). The mean percent of infections averted was 2.79 (95%SI:−10.83, 15.24) and 4.62 (95%SI:−9.5, 16.82) when PrEP uptake was 50% and 100%, respectively, and median NNT was 22.54 (95%SI:not defined, 6.45) and 27.55 (95%SI:not defined, 11.0), respectively. Providing PrEP for all uninfected individuals identified through TMP averted up to 12.68% (95%SI:0.17, 25.19) of new infections but was not efficient based on the NNT: 200.24 (95%SI:523.81, 123.23). ConclusionsProviding PrEP to individuals testing negative for HIV-1 nucleic acid after presenting to a health facility with symptoms compatible with acute HIV adds value to the TMP intervention, provided PrEP is targeted effectively and efficiently. FundingNational Institutes of Health, Sub-Saharan African Network for TB/HIV Research Excellence.

Latency to initiation of antiretroviral therapy in people living with HIV in Japan

Rapid initiation of antiretroviral therapy (ART) in HIV infection is recommended because it increases care retention rate and reduces the time to viral suppression. In Japan, although ART initiation is delayed, there is little information on the latency to ART initiation (time from HIV diagnosis to ART initiation). The present study was designed to obtain information on the latency to ART initiation in individuals with 1) acute or recent HIV infection (ARH), and with 2) advanced HIV diseases. Questionnaires were sent to 379 regional AIDS facilities requesting information on the people living with HIV (PLWH) who visited their facilities during 2020. Among 1098 new PLWH visitors, 706 were treatment-naïve patients, including 111 (15.7%) with ARH and 304 (43.1%) with advanced HIV diseases. Among those with ARH, only 8.2% received rapid ART initiation (latency to ART <2 weeks) and the time from diagnosis to virological suppression was longer than 14 weeks in 40.4%. Among those with advanced HIV diseases, 36.2% received late ART initiation (latency to ART ≧6 weeks). Our data showed that only a small proportion of PLWH with ARH in Japan received rapid ART. Furthermore, in PLWH with advanced HIV diseases in Japan, current latency to ART seems too long, though the timing of ART commencement should be tailored according to the presence/lack of opportunistic infections and accessibility to medical care. Further investigation is required to identify barriers to rapid ART initiation in Japan.

Biomarkers of central and peripheral inflammation mediate the association between HIV and depressive symptoms

People living with HIV are at increased risk for depression, though the underlying mechanisms for this are unclear. In the general population, depression is associated with peripheral and central inflammation. Given this, and since HIV infection elicits inflammation, we hypothesised that peripheral and central inflammatory biomarkers would at least partly mediate the association between HIV and depressive symptoms. People living with HIV (n = 125) and without HIV (n = 79) from the COmorBidity in Relation to AIDS (COBRA) cohort were included in this study. Participants living with and without HIV had similar baseline characteristics. All participants living with HIV were on antiretroviral therapy and were virally suppressed. Plasma, CSF, and brain MR spectroscopy (MRS) biomarkers were measured. Using logistic regression models adjusted for sociodemographic factors, we found that participants with HIV were more likely to have Any Depressive Symptoms (Patient Health Questionnaire [PHQ-9] score >4) (odds ratio [95% confidence interval] 3.27 [1.46, 8.09]). We then sequentially adjusted the models for each biomarker separately to determine the mediating role of each biomarker, with a >10% reduction in OR considered as evidence of potential mediation. Of the biomarkers analysed, MIG (−15.0%) and TNF-α (−11.4%) in plasma and MIP1-α (−21.0%) and IL-6 (−18.0%) in CSF mediated the association between HIV and depressive symptoms in this sample. None of the other soluble or neuroimaging biomarkers substantially mediated this association. Our findings suggest that certain biomarkers of central and peripheral inflammation may at least partly mediate the relationship between HIV and depressive symptoms.

Getting acute HIV infection under control

Department of Internal Medicine, OLVG, Amsterdam, The Netherlands. Correspondence to Kees Brinkman, MD, PhD, Department of Internal Medicine, OLVG, Oosterpark 9, 1091AC Amsterdam, The Netherlands. E-mail: [email protected] Received 6 February, 2023 Accepted 8 February, 2023

Cultural and religious barriers in the Middle East leading to delayed management of acute HIV case resulting in irreversible blindness: a case report.

A 26-year-old male who resides in a country in the Middle East visited the local general hospital emergency department on 17 July 2018. He presented with symptoms of persistent upper respiratory tract infection, dysphagia, and generalized fatigue. Denied any previous history of sexual contact, smoking, drinking, or using illicit drugs. This patient repeatedly attended the emergency department seeking medical attention and was treated for viral and bacterial upper respiratory tract symptoms by conservative and antibiotic therapy, yielded in short term relief but recurrence and worsening symptoms, especially dysphagia symptoms. On examination, the patient looked unwell, cachectic, and frail with normal vital signs and no positive findings on chest and abdominal examination; however, Ear Nose and Throat and oral examination revealed extensive oropharyngeal candidiasis. That is when he was suspected of having an immunodeficiency syndrome of some sort, and based on those serious findings, he was advised hospital admission for further investigations, diagnosis and management. The patient refused hospital admission against medical advice despite all the potential risks explained clearly, as he had a pre-planned family reunion holiday to Turkey, which was again strongly advised against as likely he will deteriorate while on holiday, but he went on with his plan, accordingly, oropharyngeal candidiasis was successfully treated with oral antifungal tablets, pending further investigations and definitive management. Then in 24 July 2018, he travelled to Turkey, where he developed symptoms of shortness of breath and dry a cough then he became systemically unwell and was admitted to a local hospital in Turkey where he was diagnosed with a lower respiratory tract infection and treated with intravenous antibiotics for 7 days; then on 6 August 2018, he flew back on an emergency flight to his home country, where he was admitted to the acute medical admission unit and arranged to have patient laboratory investigations. The results revealed positive HIV infection with a plasma HIV viral load was greater than 3000000 copies/ml, and advanced immunosuppression with CD3+/CD4+ T-lymphocyte was 40 cells/mm3. The social aspect of this case was apparent from denying sexual contact. The patient did not have any history of surgical operations, no family history of HIV infection, no previous blood transfusion, or use of contaminated syringes. By exclusion sexual mode of transmission is the only possible way of contracting HIV infection in this case, considering the fact that he was outside his country as single man for few years while studying. In the Middle East countries, due to religious and cultural reservations coupled with HIV diagnosis stigma, the diagnosis of the serious sexually transmitted infections such as HIV is usually delayed, as a result these patients will go on and develop late-stage disease and irreversible complications when diagnosed, entering the AIDS stage with rapid progression of irreversible complications like Cytomegalovirus, Ear Nose and Throat retinitis and blindness before they start definitive treatment. The oropharyngeal candidiasis and repeated upper and lower respiratory tract infections that are non-responding to therapy are usually red flag signs of immunosuppression, which warrants high clinical vigilance from the clinician side to take a detailed sexual history and rule out acute HIV infection by testing for it at early stages, in patients with high clinical suspicion , in addition to the other possible causes of immunosuppression. Therefore, assuring confidentiality, taking a careful sexual history and gathering data in an acceptable way for these patients and considering a holistic approach yield a better management outcome.

Patient-reported outcomes among virally suppressed people living with HIV after switching to Co-formulated bictegravir, emtricitabine and tenofovir alafenamide.

While some evidence has suggested the benefits of co-formulated bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) in improving the quality of life of people living with HIV (PLWH), patient-reported outcome studies that focus on Asian population remain scarce. We aimed to determine the changes in HIV-related symptom burden in virally-suppressed PLWH switching to B/F/TAF in a real-world setting. PLWH on stable antiretroviral therapy (ART) for ≥6 months with plasma HIV RNA <200 copies/mL who decided to switch to B/F/TAF were eligible for the study. Participants' experience with 20 symptoms were assessed using HIV Symptom Index at baseline and weeks 24 and 48. Responses were dichotomized in two ways: 1) present vs. not present; and 2) bothersome vs. not bothersome, and compared across time points. Six hundred and thirty participants (prior regimen, 94.4% integrase inhibitor-based) who completed week 48 visit were included in the analysis. Forty-eight weeks after switching to B/F/TAF, six symptoms were significantly less prevalent, and seven symptoms were significantly less bothersome. Improvement was more pronounced in participants whose prior regimen was elvitegravir-based versus dolutegravir-based. Logistic regression results showed that prior dolutegravir-based ART and pre-existing diabetes independently predicted improvement in diarrhea/loose bowels and muscle aches/joint pain, respectively. Despite the overall improvement, some symptoms persisted in a substantial proportion of participants. Virally-suppressed PLWH might benefit from a regimen switch to B/F/TAF to reduce the prevalence and level of bother of HIV-related symptoms. Nevertheless, additional multidisciplinary interventions are warranted to further alleviate the symptom burden of PLWH.

Efficacy and Safety of Two-Drug Regimens That Are Approved from 2018 to 2022 for the Treatment of Human Immunodeficiency Virus (HIV) Disease and Its Opportunistic Infections.

The human immunodeficiency virus (HIV) is a type of virus that targets the body's immune cells. HIV infection can be divided into three phases: acute HIV infection, chronic HIV infection, and acquired immunodeficiency syndrome (AIDS). HIV-infected people are immunosuppressed and at risk of developing opportunistic infections such as pneumonia, tuberculosis, candidiasis, toxoplasmosis, and Salmonella infection. The two types of HIV are known as HIV-1 and HIV-2. HIV-1 is the predominant and more common cause of AIDS worldwide, with an estimated 38 million people living with HIV-1 while an estimated 1 to 2 million people live with HIV-2. No effective cures are currently available for HIV infection. Current treatments emphasise the drug's safety and tolerability, as lifelong management is needed to manage HIV infection. The goal of this review is to study the efficacy and safety of newly approved drugs from 2018 to 2022 for the treatment of HIV by the United States Food and Drug Administration (US-FDA). The drugs included Cabotegravir and Rilpivirine, Fostemsavir, Doravirine, and Ibalizumab. From the review, switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) was shown to be noninferior to the continuation of the previous regimen, efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) in virologically suppressed adults with HIV-1. However, DOR/3TC/TDF had shown a preferable safety profile with lower discontinuations due to adverse events (AEs), lower neuropsychiatric AEs, and a preferable lipid profile. Ibalizumab was also safe, well tolerated, and had been proven effective against multiple drug-resistant strains of viruses.

Depression, Alcohol Use, and Sexual Behaviors by HIV Infection Stage and Diagnosis Timing Among STI Clinic Patients in Lilongwe, Malawi.

Understanding depression, alcohol use, and sexual behaviors according to HIV infection stage and diagnosis timing is important for HIV prevention efforts. We enrolled persons with recent infection and diagnosis (i.e., acute HIV infection (AHI) (n = 92) persons newly diagnosed seropositive (n = 360)) and persons previously diagnosed with HIV (n = 190) into a randomized controlled trial in Lilongwe, Malawi (N = 641) and estimated the prevalence of probable depression (Patient Health Questionnaire-9 ≥ 5), hazardous alcohol use (Alcohol Use Disorder Identification Test-C: men ≥ 4; women ≥ 3), and sexual behaviors (transactional sex, condomless sex). Compared with previously diagnosed participants, participants newly seropositive and those with AHI reported a higher proportion of probable depression (7%, 27%, 38%; AHI/Previous: Table Probability: 0.02, p < 0.01; AHI/New: Table Probability: <0.01, p < 0.01), hazardous alcohol use (8%, 18%, 29%; AHI/Previous and AHI/New: Table Probability: <0.01, p < 0.01), and transactional sex (5%, 14%, 20%; AHI/Previous: Table Probability: <0.01, p < 0.01; AHI/New: Table Probability: 0.06, p = 0.24), respectively. HIV prevention services addressing mental health and alcohol misuse may be particularly beneficial for persons with recent HIV infection and or diagnosis.

Per-pathogen virulence of HIV-1 subtypes A, C and D.

HIV-1 subtypes differ in their clinical manifestations and the speed in which they spread. In particular, the frequency of subtype C is increasing relative to subtypes A and D. We investigate whether HIV-1 subtypes A, C and D differ in their per-pathogen virulence and to what extend this explains the difference in spread between these subtypes. We use data from the hormonal contraception and HIV-1 genital shedding and disease progression among women with primary HIV infection study. For each study participant, we determine the set-point viral load value, CD4+ T cell level after primary infection and CD4+ T cell decline. Based on both the CD4+ T cell count after primary infection and CD4+ T cell decline, we estimate the time until AIDS. We then obtain our newly introduced measure of virulence as the inverse of the estimated time until AIDS. After fitting a model to the measured virulence and set-point viral load values, we tested if this relation varies per subtype. We found that subtype C has a significantly higher per-pathogen virulence than subtype A. Based on an evolutionary model, we then hypothesize that differences in the primary length of infection period cause the observed variation in the speed of spread of the subtypes.

What explains the poor contraction of the viral load during paediatric HIV infection?

An acute HIV infection in young children differs markedly from that in adults: Children have higher viral loads (VL), and a poor contraction to a setpoint VL that is not much lower than the peak VL. As a result, children progress faster towards AIDS in the absence of treatment. We used a classical ordinary differential equation model for viral infection dynamics to study why children have a lower viral contraction ratio than adults. We performed parameter sweeps to identify factors explaining the observed difference between children and adults. We grouped parameters associated with the host, the infection, or the immune response. Based on paediatric data available from datasets within the EPIICAL project (https://www.epiical.org/), we refuted that viral replication rates differ between young children and adults, and therefore these cannot be responsible for the low VL contraction ratios seen in children. The major differences in lowering VL contraction ratio resulted from sweeping the parameters linked to the immune response. Thus, we postulate that an ”ineffective” (late and/or weak) immune response is the most parsimonious explanation for the higher setpoint VL in young children, and hence the reason for their fast disease progression.

Genomic Evidence for the Nonpathogenic State in HIV-1-Infected Northern Pig-Tailed Macaques.

HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research.

Cohort profile: a longitudinal study of HIV infection in the central nervous system with focus on cerebrospinal fluid – the Gothenburg HIV CSF Study Cohort

PurposeIn order to enable long-term follow-up of the natural course of HIV infection in the central nervous system, a longitudinal cohort study with repeated cerebrospinal fluid (CSF) analyses at intervals...

Iterative hypothesis testing in HIV vaccine research: moving towards success.

Iterative hypothesis testing in HIV vaccine research: moving towards success.

Effect of Human Immunodeficiency Virus Infection on the Incidence and Severity of Neurological Post-Acute Sequelae of COVID-19 (S21.009)

<h3>Objective:</h3> To investigate whether HIV infection is an independent prognostic factor of neurological post-acute sequelae of COVID-19 (PASC). <h3>Background:</h3> HIV has been linked to an increase in severity of symptoms of PASC. <h3>Design/Methods:</h3> COVID-19 inpatients from a tertiary care center were collected and retrospectively studied for presence of neurological PASC symptoms, 4 weeks to up to 1 year after their first inpatient admission COVID-19. Patients with HIV and COVID-19 were compared to non-HIV COVID-19 patients. All demographic, nominal and inpatient data including length of stay, discharge, medications and lab data was compared. The proportion of patients reporting neurological PASC symptoms in HIV vs non-HIV patients with a history of COVID-19 were compared. <h3>Results:</h3> 277 patients who had an outpatient follow-up or were readmitted to the hospital were reviewed. 27 patients had HIV and 22 followed up. There was no significant difference in age between HIV and non-HIV groups (55.3±11.3 vs 52.5±18.5 p&gt;0.05) For HIV vs non-HIV patients with a history of COVID-19, numbness (18.2% vs 10.5%) paresthesias (9.1% vs 7.5%), brain fog or cognitive impairment (9.1% vs 6.7%), weakness (18.1% vs 27.1%), fatigue (31.2% vs 30.6%), headaches (18.1% vs 16.9%), changes in smell of taste (18.1% or 11.7), sleep issues or insomnia (13.6% vs 9.4%) and anxiety or depression (27.7% vs 18.0%) were reported between 4 weeks and 1 year after admission. Although there is an increased incidence of most neurological PASC symptoms in HIV compared to non-HIV, the difference did not reach significance. <h3>Conclusions:</h3> This preliminary analysis of COVID-19 patients with 1 year follow-up demonstrates that the incidence of neurological symptoms of PASC in HIV patients vs non-HIV patients did not significantly differ. The incidence reported in this study agrees with prior literature on the incidence of neurological PASC. Work is in progress expand the study size and control for concomitant neurological conditions. <b>Disclosure:</b> Mr. Jaffry has nothing to disclose. Mr. Mandava has nothing to disclose. Mr. Jaffry has nothing to disclose. Mr. Ors has nothing to disclose. Miss Shaikh has nothing to disclose. Mr. Trivedi has nothing to disclose. Ms. Faiz has nothing to disclose. Mr. Gerges has nothing to disclose. Prof. Boufadel has nothing to disclose. Dr. Souayah has received publishing royalties from a publication relating to health care.

Persistent T cell proliferation and MDSCs expansion precede incomplete CD4+ T cell recovery in people with acute HIV-1 infection with early ART

HIV-1 infection causes T cell dysfunction that cannot be fully restored by anti-retroviral therapy (ART). Myeloid-derived suppressor cells (MDSCs) expand and suppress T cell function during viral infection. In this study, we evaluated the dynamics of phenotypes and function of T cells and MDSCs and the effects of their interaction on CD4+ T cell reconstitution in people with acute HIV-1 infection (PWAH) with early ART. Flow cytometry was used to detect the phenotypic dynamics and function of T cells and MDSCs at pre-ART, 4, 24, 48, and 96 weeks of ART. We observed that T cells were hyper-activated and hyper-proliferative in PWAH at pre-ART. Early ART normalized T cell activation but not their proliferation. T cell proliferation, enriched in PD-1+ T cells, was persisted and negatively associated with CD4+ T-cell counts after ART. Moreover, M-MDSCs frequency was increased and positively correlated with T cell proliferation after 96 weeks of ART. M-MDSCs persisted and inhibited T cell proliferation ex vivo, which could be partially reversed by PD-L1 blockade. Further, we found higher frequencies of proliferative CD4+ T cells and M-MDSCs in PWAH with lower CD4+ T cell numbers (<500 cells/μL) compared to PWAH with higher CD4+ T cell numbers (>600 cells/μL) after 96 weeks of ART. Our findings indicate that persistent T cell proliferation, MDSCs expansion, and their interaction may affect CD4+ T-cell recovery in PWAH with early ART.

Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4+ T Cells.

Understanding the facilitator of HIV-1 infection and subsequent latency establishment may aid the discovery of potential therapeutic targets. Here, we report the elevation of plasma transforming growth factor β (TGF-β) during acute HIV-1 infection among men who have sex with men (MSM). Using a serum-free in vitro system, we further delineated the role of TGF-β signaling in mediating HIV-1 infection of activated and resting memory CD4+ T cells. TGF-β could upregulate both the frequency and expression of the HIV-1 coreceptor CCR5, thereby augmenting CCR5-tropic viral infection of resting and activated memory CD4+ T cells via Smad3 activation. The production of live HIV-1JR-FL upon infection and reactivation was increased in TGF-β-treated resting memory CD4+ T cells without increasing CD4 expression or inducing T cell activation. The expression of CCR7, a central memory T cell marker that serves as a chemokine receptor to facilitate T cell trafficking into lymphoid organs, was also elevated on TGF-β-treated resting and activated memory CD4+ T cells. Moreover, the expression of CXCR3, a chemokine receptor recently reported to facilitate CCR5-tropic HIV-1 infection, was increased on resting and activated memory CD4+ T cells upon TGF-β treatment. These findings were coherent with the observation that ex vivo CCR5 and CXCR3 expression on total resting and resting memory CD4+ T cells in combination antiretroviral therapy (cART)-naive and cART-treated patients were higher than in healthy individuals. Overall, the study demonstrated that TGF-β upregulation induced by acute HIV-1 infection might promote latency reservoir establishment by increasing infected resting memory CD4+ T cells and lymphoid organ homing of infected central memory CD4+ T cells. Therefore, TGF-β blockade may serve as a potential supplementary regimen for HIV-1 functional cure by reducing viral latency. IMPORTANCE Incomplete eradication of HIV-1 latency reservoirs remains the major hurdle in achieving a complete HIV/AIDS cure. Dissecting the facilitator of latency reservoir establishment may aid the discovery of druggable targets for HIV-1 cure. This study showed that the T cell immunomodulatory cytokine TGF-β was upregulated during the acute phase of infection. Using an in vitro serum-free system, we specifically delineated that TGF-β promoted HIV-1 infection of both resting and activated memory CD4+ T cells via the induction of host CCR5 coreceptor. Moreover, TGF-β-upregulated CCR7 or CXCR3 might promote HIV-1 latent infection by facilitating lymphoid homing or IP-10-mediated viral entry and DNA integration, respectively. Infected resting and central memory CD4+ T cells are important latency reservoirs. Increased infection of these cells mediated by TGF-β will promote latency reservoir establishment during early infection. This study, therefore, highlighted the potential use of TGF-β blockade as a supplementary regimen with cART in acute patients to reduce viral latency.

IL-15 enhances HIV-1 infection by promoting survival and proliferation of CCR5+CD4+ T cells.

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4+ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5+CD4+ T cells, drove their expansion, and facilitated HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15-based boosting of anti-HIV-1 immunity should carefully examine the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.

Generation and characterization of infectious molecular clones of transmitted/founder HIV-1 subtype C viruses

The genetic diversity of HIV impedes vaccine development. Identifying the viral properties of transmitted/founder (T/F) variants may provide a common vaccine target. To study the biological nature of T/F viruses, we constructed full-length clones from women detected during Fiebig stage I acute HIV-1 infection (AHI) from heterosexual male-to-female (MTF) transmission; and clones after one year of infection using In-Fusion-based cloning. Eighteen full-length T/F clones were generated from 9 women and six chronic infection clones were from 2 individuals. All clones but one were non-recombinant subtype C. Three of the 5 T/F clones and 3 chronic clones tested replicated efficiently in PBMCs and utilised CCR5 coreceptor for cell entry. Transmitted/founder and chronic infection clones displayed heterogenous in vitro replicative capacity and resistance to type I interferon. T/F viruses had shorter Env glycoproteins and fewer N-linked glycosylation sites in Env. Our findings suggest MTF transmission may select viruses with compact envelopes.

Incidence, recurrence, and prevalence of bacterial vaginosis from acute to chronic HIV infection in a prospective cohort of women in South Africa

We investigated the incidence, recurrence, prevalence, and risk factors for bacterial vaginosis (BV) diagnosis starting from acute HIV infection among South African women. The Centre for the AIDS Programme of Research in South Africa 002 study tested and treated women for BV (Nugent score 7-10) once/twice annually from acute to chronic HIV infection (2004-2020). We estimated BV incidence as the number of new cases and recurrence as the number of subsequent diagnoses per 100 person-years (PYs). We fitted Anderson-Gil Cox-proportional-hazard regression models to determine factors associated with BV incidence or recurrence. Of 235 participants, the median age at enrollment was 25 years (Inter Quartile Range [IQR] 22-29). BV prevalence at enrollment was 50.6%. BV incidence was 23.9 cases per 100 PYs, and recurrence was 51.3 cases per 100 PYs. BV incidence/recurrence was associated with younger age (<25 years: adjusted hazard ratio [aHR] 1.70, 95% confidence interval [CI] 1.27-2.27), detectable HIV viral load (aHR 1.54, 95% CI 1.27-1.87) and lower CD4 count (<350 cells/μL: aHR 1.33, 95% CI 1.01-1.76). Our findings underscore the need for early antiretroviral treatment initiation with diagnostic BV and sexually transmitted infection care, especially among younger women.