The incidence of HIV-2 infection in Spain is declining - a registry data analysis.

OBJECTIVES: HIV-2 infection is a neglected disease caused by a human retrovirus that causes AIDS more slowly than HIV-1. Infection with HIV-2 is endemic in West Africa. Given its differential features, guidelines recommend ruling out HIV-2 infection in all newly diagnosed HIV-seropositive individuals. METHODS: A national registry of HIV-2 cases was created in Spain in 1989, following the first report of three HIV-2+ individuals in Barcelona. The main demographics, clinical, and virological data are reported up to December 2023. RESULTS: A total of 424 individuals with HIV-2 infection were recorded in the Spanish registry. After a peak in 2009 when 31 cases were reported, new HIV-2 diagnoses steadily decreased. Less than 10 cases/year have been notified since the COVID-19 pandemic. In 2023, only eight cases were reported. Mean age at HIV-2 diagnosis was 44 years old, ranging from birth to 83 years. A total of 265 (62.5%) were male. Migrants predominated, being 322 (76%) Sub-Saharan Africans; however, 60 (14.2%) were native Spaniards. Heterosexual exposure was the most likely route of infection in at least 287 (67.7%) cases. A few cases could be traced to transfusions (n = 4), vertical infection (n = 2), or injection drug use (n = 7). In addition, 15 individuals (3.5%) were men who had sex with men. Coinfection with HIV-1 was recognized in 39 (9.2%) individuals. Molecular characterization of HIV-2 subtypes was performed in 139 individuals, 121 being infected with subtype A and 18 with subtype B. CONCLUSION: The annual incidence of HIV-2 infection in Spain has decreased after peaking 15 years ago, being the current number of cases below 10 per year. Three-quarters are African migrants, and two-thirds are male. Circulation of HIV-2 in Spain is limited and steadily decreasing.

Epidemic characteristics of local HIV-2 transmission across Hunan province, China.

OBJECTIVE: To elucidate the epidemiological features of HIV-2 in Hunan Province, China, utilizing sequence analysis. METHODS: Thirteen individuals diagnosed with HIV-2 infection in Hunan Province, China, from 2017 to 2023 were included in this study. Amplification of HIV-2 env and pol regions was conducted, followed by Sanger sequencing. Phylogenetic and molecular transmission network analyses were performed to delineate molecular features and transmission dynamics. RESULTS: All 14 individuals contracted HIV-2 through heterosexual intercourse, comprising 7 males and 7 females, with a median age of 58 years. Among them, three couples (HN001 and HN013, HN010 and HN011, HN008 and HN009) were identified, along with commercial sexual activity engagement reported for subject HN004. Notably, subjects HN001, HN003, HN008, and HN010 engaged in commercial sexual activities at the same location as subject HN004. Phylogenetic analysis of the pol gene revealed close proximity of sequences from all subjects to reference sequences from Gambia (Sub-type A). Employing a genetic distance threshold of 1.5 %, eight out of the 14 subjects formed a molecular transmission network, with HN002 and HN004 identified as central nodes. CONCLUSION: From 2017 to 2023, all HIV-2-infected individuals in Hunan Province, China, acquired the virus through identifiable routes, indicating transmission of similar HIV-2 strains among them.

Clinical Outcomes of Integrase Strand Transfer Inhibitors Containing Antiretroviral Therapy in HIV-2: A Narrative Review.

The human immunodeficiency virus type 2 (HIV-2) is a particular subtype of HIV, which is endemic in West Africa and is characterized by a more indolent course than HIV-1. As people living with HIV-2 (PWH-2) are at risk for the development of acquired immunodeficiency syndrome and can transmit the virus, antiretroviral therapy is usually indicated. However, the optimal treatment of HIV-2 is unknown and historically the protease inhibitors (PIs) were a regular part of therapy. Nowadays, the use of integrase strand transfer inhibitors (INSTIs) in HIV-2 is increasing but the evidence supporting this approach is limited. In this narrative review, we outline the clinical data on the use of INSTI-containing antiretroviral therapy in HIV-2. We found that in the setting of treatment-naïve PWH-2, the use of INSTIs is successful, but also noted large heterogeneity in reported outcomes and that most cohorts are small with limited follow-up time. There is a lack of studies comparing the efficacy of INSTIs to other first-line options. For treatment-experienced PWH-2, the efficacy of INSTI is highly variable.

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.

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.

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.

Interaction Between Vpx and SAMHD1, Vital for SAMHD1 Inhibition.

It was confirmed that the sterile alpha motif and HD domain 1 (SAMHD1) limits human immunodeficiency virus type 1 (HIV-1) replication. In contrast, viral protein x (Vpx) in HIV-2 and some simian immunodeficiency viruses can counteract this effect. The possible interaction between SAMHD1 and Vpx was suggested by previous studies; however, there are no data to confirm this interaction. Therefore, this study aimed to study the interaction between two proteins and the properties of Vpx protein for the first time using bioinformatic tools. Vpx and SAMHD1 sequences were obtained from the National Center for Biotechnology Information GenBank. Several software were used to define Vpx properties and the interaction between Vpx and different SAMHD1 isoforms. Our findings indicated the difference in interaction sites among different Vpx. However, in all Vpx proteins, this region is from amino acids 4 to 90. In addition, two regions (26-31 and 134-139) and two amino acids 425 and 429 in SAMHD1 are vital in the possible interaction. In addition, our analysis determined the physicochemical and immunological properties of the Vpx. Considering all factors, this study could confirm that Vpx interacts with SAMHD1, which could inhibit SAMHD1. Moreover, our findings can pave the way for future studies to express and purify Vpx in the laboratory and study this protein in vitro.

Antiviral Activity of Lenacapavir Against HIV-2 Isolates and Drug-resistant HIV-2 Mutants.

The activity of lenacapavir against HIV-1 has been extensively evaluated in vitro, but comparable data for HIV-2 are scarce. We determined the anti-HIV-2 activity of lenacapavir using single-cycle infections of MAGIC-5A cells and multicycle infections of a T cell line. Lenacapavir exhibited low-nanomolar activity against HIV-2, but was 11- to 14-fold less potent against HIV-2 in comparison to HIV-1. Mutations in HIV-2 that confer resistance to other antiretrovirals did not confer cross-resistance to lenacapavir. Although lenacapavir-containing regimens might be considered for appropriate patients with HIV-2, more frequent viral load and/or CD4 testing may be needed to assess clinical response.

Highlights from the Inaugural HIV Reservoirs and Immune Control Conference, October 1st-4th 2023, Malahide Ireland.

The inaugural FASEB HIV Reservoirs and Immune Control Conference brought researchers together from across the globe to discuss reservoir dynamics in clinical cohorts. It extended over 4 days in the seaside town of Malahide, Ireland. The scientific sessions covered a broad range of topics, including: 1) HIV pathogenesis and control, 2) reservoirs and viral expression, 3) pediatric reservoirs, 4) innate immunity and B cell responses, 5) environmental factors affecting pathogenesis, 6) loss of virologic control, and 7) HIV-2. The following article provides a brief summary of the meeting proceedings and includes a supplementary document with the meeting abstracts.

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.

Characterizing the phenotypic and genetic changes of pre-epidemic HIV-2 group F virus following serial passage in humanized mice.

HIV-2 Group F virus with an origin in NHPs was isolated from only two individuals. Two serial passages in hu-mice showed increased viral loads, CD4+ T cell decline and nonsynonymous genetic changes showing its capacity for further evolution, and spread in the human.

The HIV-2 OGH double reporter virus shows that HIV-2 is less cytotoxic and less sensitive to reactivation from latency than HIV-1 in cell culture.

A better understanding of HIV-1 latency is a research priority in HIV cure research. Conversely, little is known about the latency characteristics of HIV-2, the closely related human lentivirus. Though both viruses cause AIDS, HIV-2 infection progresses more slowly with significantly lower viral loads, even when corrected for CD4+ T cell counts. Hence a direct comparison of latency characteristics between HIV-1 and HIV-2 could provide important clues towards a functional cure. Transduction of SupT1 cells with single-round HIV-1 and HIV-2 viruses with an enhanced green fluorescent protein (eGFP) reporter showed higher levels of eGFP expression for HIV-2 than HIV-1, while HIV-1 expression appeared more cytotoxic. To compare HIV-1 and HIV-2 gene expression, latency and reactivation in more detail, we have generated HIV-2 OGH, a replication deficient, near full- length, double reporter virus that discriminates latently and productively infected cells in cell culture. This construct is based on HIV-1 OGH, and to our knowledge, first of its kind for HIV-2. Using this construct we have observed a higher eGFP expression for HIV-2, but higher losses of HIV-1 transduced cells in SupT1 and Jurkat cells and a reduced sensitivity of HIV-2 for reactivation with TNF-α. In addition, we have analysed HIV-2 integration sites and their epigenetic environment. HIV-1 and HIV-2 share a preference for actively transcribed genes in gene-dense regions and favor active chromatin marks while disfavoring methylation markers associated with heterochromatin. In conclusion the HIV-2 OGH construct provides an interesting tool for studying HIV-2 expression, latency and reactivation. As simian immunodeficiency virus (SIV) and HIV-2 have been proposed to model a functional HIV cure, a better understanding of the mechanisms governing HIV-2 and SIV latency will be important to move forward. Further research is needed to investigate if HIV-2 uses similar mechanisms as HIV-1 to achieve its integration site selectivity.

Geographic and Population Distributions of Human Immunodeficiency Virus (HIV)-1 and HIV-2 Circulating Subtypes: A Systematic Literature Review and Meta-analysis (2010-2021).

BACKGROUND: HIV poses significant challenges for vaccine development due to its high genetic mutation and recombination rates. Understanding the distribution of HIV subtypes (clades) across regions and populations is crucial. In this study, a systematic review of the past decade was conducted to characterize HIV-1/HIV-2 subtypes. METHODS: A comprehensive search was performed in PubMed, EMBASE, and CABI Global Health, yielding 454 studies from 91 countries. RESULTS: Globally, circulating recombinant forms (CRFs)/unique recombinant forms (URFs) accounted for 29% of HIV-1 strains, followed by subtype C (23%) and subtype A (17%). Among studies reporting subtype breakdowns in key populations, 62% of HIV infections among men who have sex with men (MSM) and 38% among people who inject drugs (PWIDs) were CRF/URFs. Latin America and the Caribbean exhibited a 25% increase in other CRFs (excluding CRF01_AE or CRF02_AG) prevalence between 2010-2015 and 2016-2021. CONCLUSIONS: This review underscores the global distribution of HIV subtypes, with an increasing prevalence of CRFs and a lower prevalence of subtype C. Data on HIV-2 were limited. Understanding subtype diversity is crucial for vaccine development, which need to elicit immune responses capable of targeting various subtypes. Further research is needed to enhance our knowledge and address the challenges posed by HIV subtype diversity.

Are Confirmatory Assays Reliable for HIV-1/HIV-2 Infection Differentiation? A Multicenter Study.

Immunoblots remain the gold standard for HIV-1/HIV-2 infection confirmation. However, their ability to differentiate HIV-1 from HIV-2 infection on an antigenically diversified HIV-1 and HIV-2 panel remain uncommon. We performed a multicenter study on 116 serum samples accounting for most of the diversity of HIV-1 (9 different subtypes in group M, 17 circulating recombinant forms (CRFs), and 3 group O) and HIV-2 (groups A and B), evaluating seven confirmatory assays (six commercially available assays and one in-house assay) with genotyping as the reference. The assays were INNO-LIA HIV I/II score, HIV-2 blot 1.2, HIV blot 2.2, New Lav blot I and II, Geenius, and an in-house serotyping enzyme-linked immunosorbent assay (ELISA). Among the HIV-1 samples, INNO-LIA, HIV blot 2.2, New Lav blot I, Geenius, and serotyping had comparable high sensitivities, from 98% to 100%, whereas HIV-2 blot 1.2 and New Lav blot II had high rates of "undetermined" results (85% and 95%, respectively). HIV-2 blot 1.2 and New Lav blot II misclassified 7% and 5% of HIV-1 samples as HIV-2, respectively, and HIV-2 blot 1.2 had an 8% false-negative rate. Among the HIV-2 samples, INNO-LIA, New Lav blot II, HIV-2 blot 1.2, and serotyping had high sensitivities, from 96% to 100%. HIV blot 2.2 misclassified 17% of HIV-2 samples as HIV-1/HIV-2 dual infections. New Lav blot I misclassified 19% of HIV-2 samples as HIV-1 with a high (81%) undetermined rate, and Geenius misclassified 2% as HIV-1 and 7% as untypeable HIV positive. For HIV-1/HIV-2 dual infection, the results were less sensitive, with at most 87.5% for INNO-LIA and Geenius and 75% for HIV blot 2.2 and serotyping. Overall, confirmatory assays remain useful for most cases, with the exception of HIV-1/HIV-2 dual-infection suspicion.

Safety and Efficacy of Triple Therapy With Dolutegravir Plus 2 Nucleoside Reverse Transcriptase Inhibitors in Treatment-Naive Human Immunodeficiency Virus Type 2 Patients: Results From a 48-Week Phase 2 Study.

BACKGROUND: Integrase strand transfer inhibitor-based regimens are recommended for first-line therapy in human immunodeficiency virus type 2 (HIV-2). Nonetheless, dolutegravir (DTG) clinical trial data are lacking. METHODS: We conducted a phase 2, single-arm, open-label trial to evaluate the safety and efficacy of a triple therapy regimen that included DTG in persons with HIV-2 (PWHIV-2) in Portugal. Treatment-naive adults receive DTG in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs). Treatment efficacy was evaluated by the proportion of patients who achieved a plasma viral load (pVL) <40 copies/mL and/or by the change from baseline in CD4+ T-cell count and in CD4/CD8 ratio at week 48. RESULTS: A total of 30 patients were enrolled (22 women; median age, 55 years). At baseline, 17 (56.7%) individuals were viremic (median, pVL 190 copies/mL; interquartile range [IQR], 99-445). The median CD4 count was 438 cells/µL (IQR, 335-605), and the CD4/CD8 ratio was 0.8. Three patients discontinued the study. At week 48, all participants (27) had pVL <40 copies/mL. No virological failures were observed. Mean changes in CD4 count and CD4/CD8 ratio at week 48 were 95.59 cells/µL (95% confidence interval [CI], 28-163) and 0.32 (95% CI, .19 to .46). The most common drug-related adverse events were headache and nausea. One participant discontinued due to central nervous system symptoms. No serious adverse events were reported. CONCLUSIONS: DTG plus 2 NRTIs is safe and effective as first-line treatment for PWHIV-2 with a tolerability profile previously known. No virological failures were observed that suggest a high potency of DTG in HIV-2 as occurs in HIV-1. CLINICAL TRIALS REGISTRATION: M NCT03224338.

It Was Not the Perfect Storm: The Social History of the HIV-2 Virus in Guinea-Bissau.

The perfect storm model that was elaborated for the HIV-1M pandemic has also been used to explain the emergence of HIV-2, a second human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) that became an epidemic in Guinea-Bissau, West Africa. The use of this model creates epidemiological generalizations, ecological oversimplifications and historical misunderstandings as its assumptions-an urban center with explosive population growth, a high level of commercial sex and a surge in STDs, a network of mechanical transport and country-wide, en masse mobile campaigns-are absent from the historical record. This model fails to explain how the HIV-2 epidemic actually came about. This is the first study to conduct an exhaustive examination of sociohistorical contextual developments and align them with environmental, virological and epidemiological data. The interdisciplinary dialogue indicates that the emergence of the HIV-2 epidemic piggybacked on local sociopolitical transformations. The war's indirect effects on ecological relations, mobility and sociability were acute in rural areas and are a key to the HIV-2 epidemic. This setting had the natural host of the virus, the population numbers, the mobility trends and the use of technology on a scale needed to foster viral adaptation and amplification. The present analysis suggests new reflections on the processes of zoonotic spillovers and disease emergence.