Salvage Therapy Including Foscarnet and Ibalizumab for Multidrug-Resistant Human Immunodeficiency Virus Type 2 Infection.

We evaluated Ibalizumab (IBA)-containing standardized optimized salvage regimen (with or without a 4-week foscarnet induction) in individuals harboring multidrug-resistant human immunodeficiency virus type 2 (HIV-2). Nine were included; 2 achieved virological suppression after foscarnet induction with a sustained suppression at Week 24 after IBA initiation, and an additional individual at Week 24 after Ibalizumab initiation.

The development, evaluation, performance, and validation of micro-PCR and extractor for the quantification of HIV-1 &-2 RNA.

HIV infection has been a global public health threat and overall reported ~ 40 million deaths. Acquired immunodeficiency syndrome (AIDS) is attributed to the retroviruses (HIV-1/2), disseminated through various body fluids. The temporal progression of AIDS is in context to the rate of HIV-1 infection, which is twice as protracted in HIV-2 transmission. Q-PCR is the only available method that requires a well-developed lab infrastructure and trained personnel. Micro-PCR, a portable Q-PCR device, was developed by Bigtec Labs, Bangalore, India. It is simple, accurate, fast, and operationalised in remote places where diagnostic services are inaccessible in developing countries. This novel micro-PCR determines HIV-1 and HIV-2 viral load using a TruePrep™ extractor device for RNA isolation. Five ml blood samples were collected at the blood collection centre at AIIMS, New Delhi, India. Samples were screened for serology, and a comparison of HIV-1/2 RNA was done between qPCR and micro-PCR in the samples. The micro-PCR assay of HIV-RNA has compared well with those from real-time PCR (r = 0.99, i < 0.002). Micro-PCR has good inter and intra-assay reproducibility over a wide dynamic range (1.0 × 102-1.0 × 108 IU/ml). The linear dynamic range was 102-108 IU/ml. The clinical and analytical specificity of the assay was comparable, i.e., 100%. Intra-assay and inter-assay coefficients of variation ranged from 1.17% to 3.15% and from 0.02% to 0.46%, respectively. Moreover, due to the robust, simple, and empirical method, the Probit analysis has also been done for qPCR LODs to avoid uncertainties in target recoveries. The micro-PCR is reliable, accurate, and reproducible for early detection of HIV-1 and HIV-2 viral loads simultaneously. Thus, it can easily be used in the field and in remote places where quantification of both HIV-1/2 is not reachable.

Clinical presentations and outcomes of HIV-1 and HIV-2 among infected children in Guinea-Bissau: a nationwide study.

OBJECTIVES: Disease progression, loss to follow-up, and mortality of HIV-2 compared with HIV-1 in children is not well understood. This is the first nationwide study reporting outcomes in children with the two HIV types in Guinea-Bissau. STUDY DESIGN: Nationwide retrospective follow-up study. METHODS: This is a retrospective follow-up study among HIV-infected children <15 years at nine ART centers from 2006 to 2021. Baseline parameters and disease outcomes for children with HIV-2 and HIV-1 were compared. RESULTS: The annual number of children diagnosed with HIV peaked in 2017. HIV-2 (n = 64) and HIV-1 (n = 1945) infected children were different concerning baseline median age (6.5 vs 3.1 years, P < 0.01), but had similar levels of severe immunodeficiency (P = 0.58) and severe anemia (P = 0.26). Within the first year of follow-up, 36.3% were lost, 5.9% died, 2.7% had transferred clinic, and 55.2% remained for follow-up. Mortality (HR = 1.05 95% CI: 0.53-2.08 for HIV-2) and attrition (HR = 0.86 95% CI: 0.62-1.19 for HIV-2) rates were similar for HIV types. CONCLUSIONS: The decline in children diagnosed per year since 2017 is possibly due to lower HIV prevalence, lack of HIV tests, and the SARS-CoV-2 epidemic. Children with HIV-2 were twice as old as HIV-1 infected when diagnosed, which suggests a slower disease progression. However, once they develop immunosuppression mortality is similar.

Sensitivity and specificity of the new Bio-Rad HIV screening test, Access HIV combo V2.

Diagnosing of human immunodeficiency virus (HIV) types 1 and 2 requires a screening with a highly sensitive and specific enzyme immunoassay and a low detection limit for the HIV-1 p24 antigen to minimize the diagnostic window. The objective of the study was to determine the sensitivity, specificity, and p24 limit of detection of the Access HIV combo V2 assay. Retrospective part of sensitivity: 452 HIV-1 positive samples from 403 chronic (9 different HIV-1 group M subtypes, 22 different HIV-1 group M CRFs, and 3 HIV-1 group O), 49 primary HIV-1 infections, 103 HIV-2 positive samples assessed at Pitié-Salpêtrière Hospital, 600 untyped HIV-1, 10 subtype-D, and 159 untyped HIV-2 samples assessed in Bio-Rad Laboratories. Prospective part of clinical specificity: all consecutive samples in two blood donor facilities and Pitié-Salpêtrière (6,570 patients) tested with Access HIV combo V2 and respectively Prism HIV O Plus (Abbott) or Architect HIV Ag/Ab Combo (Abbott) for Ag/Ab screening, and Procleix Ultrio (Gen Probe) for HIV RNA screening. Limit of detection for p24 antigen was assessed on recombinant virus-like particles (10 HIV-1 group M subtypes/CRFs, HIV-1 group O). Sensitivity [95% confidence interval (CI)] of Access HIV combo V2 was 100% (99.63-100) for HIV-1 chronic infection, 100% (98.55-100) for HIV-2 chronic infection, and 100% (93.00-100) for HIV-1 primary infection. Specificity (95% CI) was 99.98 (99.91-100). Limit of detection for p24 antigen was around 0.43 IU/mL [interquartile range (0.38-0.56)], and consistent across the 11 analyzed subtypes/CRFs. Hence, with both high sensitivity and specificity, Access HIV combo V2 is a suitable screening assay for HIV-1/2 infection. IMPORTANCE: Bio-Rad is one of the leading human immunodeficiency virus (HIV) screening test manufacturers. This laboratory released in 2021 their new version of the Access combo HIV test. However, to date, there have been no studies regarding its performance, especially its limit of detection of the diverse p24 antigen. We present the sensitivity (chronic and primary HIV-1 infection and HIV-2 chronic infection), specificity (blood donors and hospitalized patients), and raw data for the p24/seroconversion panels the manufacturer gave to the European agencies.

Spatial resolution of HIV-1 post-entry steps in resting CD4 T cells.

Resting CD4 T cells resist productive HIV-1 infection. The HIV-2/simian immunodeficiency virus protein viral accessory protein X (Vpx) renders these cells permissive to infection, presumably by alleviating blocks at cytoplasmic reverse transcription and subsequent nuclear import of reverse-transcription/pre-integration complexes (RTC/PICs). Here, spatial analyses using quantitative virus imaging techniques reveal that HIV-1 capsids containing RTC/PICs are readily imported into the nucleus, recruit the host dependency factor CPSF6, and translocate to nuclear speckles in resting CD4 T cells. Reverse transcription, however, remains incomplete, impeding proviral integration and viral gene expression. Vpx or pharmacological inhibition of the deoxynucleotide triphosphohydrolase (dNTPase) activity of the restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) increases levels of nuclear reverse-transcribed cDNA and facilitates HIV-1 integration. Nuclear import and intranuclear transport of viral complexes therefore do not pose important blocks to HIV-1 in resting CD4 T cells, and the limitation to reverse transcription by SAMHD1's dNTPase activity constitutes the main pre-integration block to infection.

External quality assessment to support the WHO ProSPeRo study for the evaluation of two dual HIV/syphilis point-of-care tests in seven countries.

BACKGROUND: Sexually transmitted infections (STIs) such as syphilis and HIV remain to be a significant public health issue worldwide. Dual rapid point-of-care tests (POCTs) have shown promise for detecting antibodies to HIV and syphilis but have not been fully evaluated in the field. Our study supported the WHO ProSPeRo study on Sexually Transmitted Infection Point-of-Care Testing (STI POCT) by providing external quality assessment (EQA) for HIV and syphilis testing in reference laboratories and their associated clinical sites in seven countries. METHODS: HIV/syphilis serum liquid and dried tube specimen (DTS) panels were prepared by CDC. Liquid panels were distributed to the reference laboratories for three rounds of testing using commercially and locally available laboratory-based serological tests. DTS panels were sent to the clinical testing sites for 8 rounds of POC testing using the Abbott SD BIOLINE HIV/Syphilis Duo test (hereafter referred to as SD BIOLINE) and the Chembio Dual Path Platform (DPP) HIV-Syphilis assay. EQA panels were tested at CDC using the Rapid Plasma Reagin (RPR) test and the Treponema pallidum Particle Agglutination assay (TP-PA) for syphilis antibodies. Genetic Systems HIV-1/HIV-2 Plus O EIA, Geenius HIV Supplemental Assay and the Oraquick Advance HIV test were used to detect HIV antibodies in the EQA panels. Results from the reference laboratories and POCT sites were compared to those obtained at the CDC and a percentage agreement was calculated. RESULTS: Qualitative RPR and TP-PA performed at the reference laboratories demonstrated 95.4-100% agreement with CDC results while quantitative RPR and TP-PA tests demonstrated 87.7% and 89.2% agreement, respectively. A 93.8% concordance rate was observed for qualitative HIV testing in laboratories. EQA testing at clinical sites using dual tests showed 98.7% and 99.1% agreement for detection of HIV antibodies and eight out of 10 sites had > 95.8% agreement for syphilis testing. However, two clinical sites showed only 65.0-66.7% agreement for SD BIOLINE and 84.0-86.7% for DPP, respectively, for syphilis testing. CONCLUSIONS: Overall, laboratories demonstrated high EQA performance in this study. Both HIV/syphilis POCTs gave expected results in the clinic-based evaluations using DTS. However, testing errors were identified in a few testing sites suggesting the necessity for continuous training and monitoring the quality of POC testing.

Laboratory-based evaluation of the 4th-generation AlereTM HIV Combo rapid point-of-care test.

BACKGROUND: Mozambique is a high-prevalence country for HIV and early detection of new HIV infections is crucial for control of the epidemic. We aimed to evaluate the accuracy of the 4th-generation rapid diagnostic test (RDT) AlereTM HIV Combo in detecting acute and seroconverted HIV-infection, among sexually-active women attending three clinical health centers in Maputo, Mozambique. METHODS: Women aged 14-55 years (n = 920) seeking care at the Mavalane Health Area, Maputo (February 2018-January 2019) were included, and blood specimens sampled. Sociodemographic and sexual behavior data were collected. Point-of-care HIV testing was performed using Alere DetermineTM HIV-1/2 and Uni-GoldTM HIV-1/2. All samples were also tested using Enzygnost® HIV Integral 4 and Innotest® HIV Antigen mAb in laboratory. The 4th-generation RDT AlereTM HIV Combo was evaluated on serum samples in the laboratory. Finally, Innotest® HIV Antigen mAb, Enzygnost® HIV Integral 4 (Ag/Ab), and HIV RNA quantification acted as gold standard assays in the evaluation of AlereTM HIV Combo test for HIV antigen detection (in clinical samples and in three HIV-1 seroconversion panels). RESULTS: The antibody component of the 4th generation AlereTM HIV Combo RDT demonstrated a sensitivity and specificity of 100% examining clinical samples. However, the test did not detect HIV p24 antigen in any clinical samples, while Innotest® HIV Antigen mAb, verified by Enzygnost® HIV Integral 4 (Ag/Ab) and/or HIV RNA quantification, detected HIV antigen in six clinical samples. Furthermore, the AlereTM HIV Combo RDT had a low sensitivity in the detection of HIV p24 antigen in seroconversion panels. The HIV prevalence among the examined women was 17.8%. CONCLUSIONS: The 4th-generation RDT AlereTM HIV Combo showed similar sensitivity to the 3rd-generation RDTs to detect seroconverted HIV-infections. However, the sensitivity for detection of HIV p24 antigen and diagnosing acute HIV infections, before seroconversion, was low. There is an urgent need to develop and evaluate simple and affordable POC tests with high sensitivity and specificity for diagnosing individuals with acute HIV infection in resource-limited settings with high HIV prevalence.

Evaluation of the VioOne HIV profile supplemental assay.

HIV is an ongoing global epidemic with estimates of more than a million new infections occurring annually. To combat viral spread, continuous innovations in areas including testing and treatment are necessary. In the United States, the Centers for Disease Control and Prevention recommend that laboratories follow an HIV testing algorithm that first uses a US Food and Drug Administration approved immunoassay to detect antibodies to HIV-1 or HIV-2 as well as HIV-1 p24 antigen in serum or plasma samples. An initially reactive specimen is tested by a supplemental assay for confirmation and to differentiate antibodies to HIV-1 or HIV-2. There are few Food and Drug Administration (FDA)-approved supplemental differentiation tests currently available. A multicenter investigation was conducted to determine the clinical performance for two independent versions of the Avioq VioOne HIV Profile Supplemental Assay (Avioq, Inc., Research Triangle Park, NC). The performance of both assay versions compared favorably with the performance parameters for the Geenius HIV 1/2 Supplemental Assay as published in that assay package insert (Bio-Rad Laboratories, Hercules, CA), the current gold standard for HIV supplemental testing. When comparing the two VioOne assays, version 2 (lacking HIV-2 p27 antibody detection) demonstrated improved reproducibility, specificity, and sensitivity as compared to its predecessor. IMPORTANCE We evaluated the reproducibility, sensitivity, and specificity data for two versions of the VioOne HIV Profile Supplemental Assay and compared these results back to similar results for the Geenius HIV 1/2 Supplemental Assay that are publicly available. Our study concluded that the VioOne HIV Profile Supplemental Assay compared favorably with the Geenius HIV 1/2 Supplemental Assay, thus providing an additional option for clinical laboratories to improve and expand their HIV testing capabilities.

Natural course of AIDS following HIV-2 infection.

In a 21-year-old female, AIDS following infection with HIV-2 was diagnosed alongside an HIV-associated high-grade B cell lymphoma. Treatment of HIV-2 with dolutegravir, emtricitabine, and tenofovir resulted in viral suppression and slow recovery of CD4 cell counts. Treatment of lymphoma caused significant adverse effects but led to complete remission. The patient denied sexual activity and intravenous drug abuse. The patient had been born to an HIV-2-positive mother but appropriate perinatal testing based on national guidelines had remained negative. This case recapitulates the natural course of HIV-2 infection.

Membrane-permeable tenofovir-di- and monophosphate analogues.

The development of new antiviral agents such as nucleoside analogues or acyclic nucleotide analogues (ANPs) and prodrugs thereof is an ongoing task. We report on the synthesis of three types of lipophilic triphosphate analogues of (R)-PMPA and dialkylated diphosphate analogues of (R)-PMPA. A highly selective release of the different nucleotide analogues ((R)-PMPA-DP, (R)-PMPA-MP, and (R)-PMPA) from these compounds was achieved. All dialkylated (R)-PMPA-prodrugs proved to be very stable in PBS as well as in CEM/0 cell extracts and human plasma. In primer extension assays, both the monoalkylated and the dialkylated (R)-PMPA-DP derivatives acted as (R)-PMPA-DP as a substrate for HIV-RT. In contrast, no incorporation events were observed using human polymerase γ. The dialkylated (R)-PMPA-compounds exhibited significant anti-HIV efficacy in HIV-1/2 infected cells (CEM/0 and CEM/TK-). Remarkably, the dialkylated (R)-PMPA-MP derivative 9a showed a 326-fold improved activity as compared to (R)-PMPA in HIV-2 infected CEM/TK- cells as well as a very high SI of 14,000. We are convinced that this study may significantly contribute to advancing antiviral agents developed based on nucleotide analogues in the future.

Evaluating the sensitivity and specificity of Determine™ HIV-1/2 rapid test using a 0.01M phosphate-buffered saline produced at the Medical Research Council Unit The Gambia for the diagnosis of HIV.

BACKGROUND: Human immunodeficiency virus (HIV) rapid diagnostic tests (RDTs) are widely used. However, buffer stockouts commonly lead to utilising non-approved liquids, resulting in errors. Our aim was to evaluate the diagnostic accuracy of an alternative buffer. METHODS: Paired Determine HIV-1/2 rapid tests with commercial buffer and locally produced 0.01M phosphate-buffered saline (PBS) were performed on consecutive consenting individuals requiring HIV testing. Serum samples were sent for confirmation through the local gold-standard algorithm (Murex HIV Ag/Ab, Hexagon HIV with/without Geenius HIV 1/2). Test accuracy, κ and exact McNemar's test were also carried out. RESULTS: Of 167 participants, 137 had confirmatory testing. The sensitivity of the Determine HIV-1/2 test using PBS compared with the gold standard was 100% (95% confidence interval [CI] 90.5 to 100) with a specificity of 98% (95% CI 92.9 to 99.8). The κ value was 0.94 compared with the gold standard and 0.92 compared with the Determine HIV-1/2 test using the commercial buffer. McNemar's test showed no evidence of differing sensitivities. Due to operational constraints, the study included 37 of the 49 positive cases as determined by the sample size calculation, resulting in an attained power of 80% instead of the intended 90%. CONCLUSIONS: These results suggest that 0.01M PBS is an alternative solution for Determine HIV-1/2 when buffer stockouts occur.

The HIV-2 proviral landscape is dominated by defective proviruses.

BACKGROUND: Compared with HIV-1 infection, HIV-2 infection is associated with a slower progression to AIDS. Understanding the persistence of HIV-2 infection might inform the mechanisms responsible for differences in the pathogenicity of HIV-2 versus HIV-1. METHODS: In this study, we analyzed the genetic composition of the proviral reservoir in archived blood samples collected from 13 untreated HIV-2-infected adults from Senegal. We used single-genome, near-full-length individual proviral sequencing (FLIP-Seq) to assess the relative frequency of intact and defective proviruses. RESULTS: Ten out of 13 (77%) study participants demonstrated virologic suppression (<90 HIV RNA copies/ml) while the remaining 3 (23%) had detectable HIV RNA. We obtained 363 proviral sequences from peripheral blood mononuclear cells (PBMCs) from the 13 study participants. Within these sequences, 342 (94%) defective proviruses were detected. Twenty-one (6%) intact proviruses were detected from three study participants, with one study participant displaying a large clone consisting of 16 genome-intact sequences. CONCLUSION: This data suggests that similar to HIV-1 infection, the proviral landscape of HIV-2 is dominated by defective proviruses.

Recent HIV-1 infection in Israel 2017-2021: Evaluation of geenius and HIV-1/2 combo assays for identifying recent infection detected by Sedia assay and assessment of factors related to recent infection: Recent HIV-1 infection in Israel.

BACKGROUND: Estimating HIV-1 recency of infection for incidence and local outbreaks detection usually involves specifically designed assays. Here, we established an approach to identify recent infections, estimate their rate, and assess potential risk factors. METHODS: Randomly selected HIV-1 positive samples (n = 382) collected in 2017-2021 were tested by Sedia and compared to the results of Geenius recency algorithm and the S/CO values of the HIV-1/2 Combo assay. Using Geenius and Combo recency verdict, we assessed all cases diagnosed in 2017-2021. Related factors were further assessed. RESULTS: While Geenius and Combo had a sensitivity of 65.9 % and 89.30 %, respectively, and specificity of 96 % and 90 %, respectively, compared to Sedia, higher concordance (97.2 %) and kappa (>0.9) were observed when the verdict of both assays together was compared to Sedia. Using this approach, 15.3 % (238/1548) of individuals diagnosed in 2017-2021 were defined as recently infected. In multivariate analysis, recent diagnosis was mainly associated with men who have sex with men (MSM) and with birthplace in Israel, Western/Central Europe, or North America. CONCLUSIONS: Only 15.3 % of infections in 2017-2021, mainly in MSM and Israeli/Western countries-born individuals, were diagnosed early. Regular diagnostic assays have a potential to identify and monitor trends in recent infections.

m-PIMA™ HIV1/2 VL: A suitable tool for HIV-1 and HIV-2 viral load quantification in West Africa.

Point-of-Care for HIV viral RNA quantification seems to be a complementary strategy to the existing conventional systems. This study evaluated the performance of the m-PIMA™ HIV1/2 Viral Load for the quantification of both HIV-1 and HIV-2 RNA viral load. A total of 555 HIV-1 and 90 HIV-2 samples previously tested by Abbott RealTime HIV-1 (Abbott, Chicago, USA) and Generic HIV-2® Charge virale (Biocentric, France) were tested using the m-PIMA™ HIV1/2 Viral Load at the HIV National Reference lab in Senegal. For HIV-1, Pearson correlation and Bland-Altman plots showed a coefficient r = 0.97 and a bias of -0.11 log10 copies/ml (95% confidence interval [CI]: -0.086 to -0.133 log10 copies/ml) for the m-PIMA™ HIV1/2 Viral Load, respectively. Sensitivity and specificity at 3 log10 copies/ml (threshold of virological failure) were 93.6% (95%[CI]: 91.5% to 95.6%) and 99.1% (95%[CI]: 98.3% to 99.9%), respectively. For HIV-2, a correlation of r = 0.95 was also noted with a bias of - 0.229 log10 copies/ml (95%[CI]: -0.161 to -0.297 log10 copies/ml). Sensitivity and specificity at 3 log10 copies/ml were 97.6% (95%[CI]: 94.3% to 100%) and 93.9% (95%[CI]: 88.9% to 98.8%), respectively. These results confirmed that m-PIMA™ HIV1/2 VL could be a good alternative for HIV-1 and HIV-2 viral load testing in decentralized settings in Senegal.

Evaluation of the sensitivity and specificity of rapid human immunodeficiency virus (HIV)1 and 2 test kits commonly used in Nigeria

The sensitivity and specificity of five rapid HIV antibody test kits commonly used in Nigeria were evaluated. The kits were selected based on their high percentage frequency of use as compared to others. A total of 100 EIA HIV-1and RNA HIV-1 positive sera were used as positive gold standard; while 100 EIA HIV-1 and RNA HIV-1 negative sera were used as negative gold standard. The positive gold standard sera were pooled; serially diluted and analysed to determine the sensitivities of the kits. The methods used were strictly as provided by the manufacturers. Of the 100 positive gold standard serum samples used; Immunocomb-II gave false negative results with 10 (Sensitivity = 90); while HIV-SAV; Hexagon; Determine and SD-Bioline were false negative with 12 specimens; representing 88 sensitivity for each. On the other hand; of the 100 negative gold standard sera; Immunocomb-II gave 6 false positive results (Specificity = 94); HIV-SAV 12 (Specificity = 88); Hexagon 2 (Specificity = 98); Determine 12 (Specificity = 88); while SD-Bioline had no false positive result (specificity = 100). In analytical sensitivity; Immunocomb-II detected the highest serum titre of 30 000; making it the most sensitive. Two of the five test kits (Immunocomb and SD-Bioline) demonstrated excellent analytical sensitivity and specificity respectively. The two could be recommended for use as combination test algorithms instead of EIA/Western Blot algorithm; which is time-consuming; expensive and often not technically feasible in a developing country like ours. This study shows that not all the analytical performance indices cited in the literature from the manufacturers of diagnostic kits are necessarily reproducible in end-user laboratories

Macrophage-Derived Factors with the Potential to Contribute to Pathogenicity of HIV-1 and HIV-2: Role of CCL-2/MCP-1.

Human immunodeficiency virus type 2 (HIV-2) is known to be less pathogenic than HIV-1. However, the mechanism(s) underlying the decreased HIV-2 pathogenicity is not fully understood. Herein, we report that ß-chemokine CCL2 expression was increased in HIV-1-infected human monocyte-derived macrophages (MDM) but decreased in HIV-2-infected MDM when compared to uninfected MDM. Inhibition of CCL2 expression following HIV-2 infection occurred at both protein and mRNA levels. By microarray analysis, quantitative PCR, and Western blotting, we identified that Signal Transducer and Activator of Transcription 1 (STAT1), a critical transcription factor for inducing CCL2 gene expression, was also reduced in HIV-2-infected MDM. Blockade of STAT1 in HIV-infected MDM using a STAT1 inhibitor significantly reduced the production of CCL2. In contrast, transduction of STAT1-expressing pseudo-retrovirus restored CCL2 production in HIV-2-infected MDM. These findings support the concept that CCL2 inhibition in HIV-2-infected MDM is meditated by reduction of STAT1. Furthermore, we showed that STAT1 reduction in HIV-2-infected MDM was regulated by the CUL2/RBX1 ubiquitin E3 ligase complex-dependent proteasome pathway. Knockdown of CUL2 or RBX1 restored the expression of STAT1 and CCL2 in HIV-2-infected MDM. Taken together, our findings suggest that differential regulation of the STAT1-CCL2 axis may be one of the mechanisms underlying the different pathogenicity observed for HIV-1 and HIV-2.

Genotypic and Phenotypic Characterization of Replication-Competent HIV-2 Isolated from Controllers and Progressors.

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.

HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection.

IMPORTANCE: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.