HIV-1

Human immunodeficiency virus is the defining pathogen of modern clinical virology. It is the cause of acquired immunodeficiency syndrome (AIDS), and four decades after its discovery it remains one of the most intensively studied organisms in biology: the source of the antiretroviral drug classes, the resistance-testing infrastructure, and much of the molecular diagnostics that the rest of the discipline now takes for granted. Around 39 million people are living with HIV worldwide, the great majority in sub-Saharan Africa, where HIV-1 group M subtype C predominates. Despite four decades of intensive vaccine research no licensed vaccine yet exists, but biomedical prevention (treatment as prevention, pre-exposure prophylaxis (PrEP) with oral tenofovir / emtricitabine, long-acting cabotegravir, and six-monthly lenacapavir) has transformed the prospects for ending the pandemic as a public-health threat.

Discovery and historical significance

AIDS was first recognised in 1981, when clusters of Pneumocystis pneumonia and Kaposi sarcoma in previously healthy young men were reported in the United States. The causative virus was isolated in 1983 by Françoise Barré-Sinoussi and Luc Montagnier at the Institut Pasteur, who called it lymphadenopathy-associated virus (LAV); Robert Gallo’s group described the same agent as HTLV-III the following year. The unifying name human immunodeficiency virus was adopted in 1986, and the Institut Pasteur discovery was recognised with the 2008 Nobel Prize in Physiology or Medicine awarded to Barré-Sinoussi and Montagnier. A second, less pathogenic virus (HIV-2) was identified in West Africa in 1986.

Molecular phylogenetics has since reconstructed the origin of the pandemic. HIV-1 arose from multiple independent cross-species transmissions of simian immunodeficiency viruses in central-west Africa, with the pandemic group M lineage tracing to a chimpanzee virus (SIVcpz) that crossed into humans in the early twentieth century and diversified in and around Kinshasa before spreading globally. That zoonotic, recombination-prone origin explains the extraordinary genetic diversity that still shapes diagnosis, treatment and vaccine development today.

The development of effective antiretroviral therapy (ART) proceeded in waves. Zidovudine (the first nucleoside reverse transcriptase inhibitor) was licensed in 1987, with limited durable effect as monotherapy. The introduction of highly active antiretroviral therapy (HAART) in 1996 (combining at least three drugs to fully suppress replication and prevent resistance) transformed HIV from a uniformly fatal illness to a manageable chronic disease. Integrase strand-transfer inhibitors (raltegravir 2007; dolutegravir 2013; bictegravir 2018) have become the backbone of modern first-line therapy. The United States President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund, both established in 2003, underwrote the scale-up of ART access in sub-Saharan Africa from the mid-2000s. The 2010s saw the licensing of effective biomedical prevention tools: oral PrEP (2012), long-acting cabotegravir PrEP (2021), and six-monthly lenacapavir PrEP (2024). U=U (“undetectable equals untransmittable”) was endorsed in 2016 as a foundational principle of HIV prevention.

Classification, structure, and genome

Classification

HIV-1 belongs to the family Retroviridae, subfamily Orthoretrovirinae, genus Lentivirus, the genus of slow, persistent, immunosuppressive animal and human retroviruses. Under the binomial species nomenclature that the International Committee on Taxonomy of Viruses (ICTV) adopted across all viruses, the species was renamed Lentivirus humimdef1 in the 2024 taxonomy update; the everyday name “HIV-1” remains correct and is unaffected, exactly as “measles virus” persists alongside Morbillivirus hominis.

There are two human immunodeficiency viruses. HIV-1 is responsible for the global pandemic. HIV-2, largely confined to West Africa (with foci in parts of India and in Portugal), descends from the sooty mangabey virus (SIVsm), shares only about 50 to 60% of its sequence with HIV-1, and is less transmissible and slower to progress. The distinction is clinically important: HIV-2 is intrinsically resistant to the non-nucleoside reverse transcriptase inhibitors and to enfuvirtide, and several protease inhibitors are less active against it, so regimen choice and the viral-load assay used must both account for it.

HIV-1 itself is divided into four groups (M, N, O and P), each the product of a separate primate-to-human transmission (M and N from chimpanzee SIVcpz; O and P from gorilla SIVgor). Group M causes essentially the entire pandemic and is subdivided into subtypes A to D, F to H, J and K, along with more than forty circulating recombinant forms (CRFs) generated when a person is co-infected with two subtypes. Subtype C predominates in southern Africa and India and accounts for roughly half of all infections worldwide, making it the single most prevalent subtype; subtype B dominates Europe and the Americas, and CRF01_AE dominates South-East Asia. Because the reverse transcriptase is error-prone, the virus exists within each infected person not as a single sequence but as a swarm of related variants (a quasispecies), which is the raw material for both immune escape and drug resistance.

The genus Lentivirus also contains the simian immunodeficiency viruses of primates (SIVcpz, SIVsm, SIVgor, and others) and the lentiviruses of cats (feline immunodeficiency virus), cattle (bovine immunodeficiency virus), horses (equine infectious anaemia virus), and small ruminants (visna-maedi virus). Many of these have been used as models for HIV biology and antiviral evaluation.

Virion structure

The mature particle is roughly spherical and about 120 nm across. Its outermost layer is a lipid bilayer envelope, acquired from the host plasma membrane, studded with relatively sparse trimeric Env spikes, each a trimer of gp120 / gp41 heterodimers. Immediately beneath the envelope is a shell of matrix protein (p17). Within sits the structure that gives the particle its signature appearance on electron microscopy: a conical capsid built of p24 arranged as a fullerene cone, a non-icosahedral, non-helical geometry. The capsid encloses the two RNA copies coated by nucleocapsid, together with the reverse transcriptase, integrase, protease, Vpr and a host tRNA that primes reverse transcription.

Genome organisation

The genome is approximately 9.7 kb of positive-sense single-stranded RNA, present as two identical copies (the virus is diploid), flanked by two long terminal repeats. The 5’ LTR contains the promoter and enhancer that drive transcription; the 3’ LTR provides the polyadenylation signal.

Three genes encode the structural and enzymatic proteins, processed from large precursor polyproteins:

• gag yields the matrix protein (MA, p17, which lines the inner envelope and directs Env incorporation), the capsid protein (CA, p24, which forms the conical core), the nucleocapsid (NC, p7, which binds and packages the genomic RNA), and p6 (which recruits the budding machinery and Vpr).
• pol yields the three enzymes that are the classic drug targets: protease (PR, an aspartyl protease that cleaves the precursors during maturation), reverse transcriptase (RT, a p66 / p51 heterodimer with RNA-dependent DNA polymerase and RNase H activity), and integrase (IN).
• env yields the gp160 precursor, cleaved into the surface glycoprotein gp120 (SU, which binds the receptor) and the transmembrane glycoprotein gp41 (TM, which drives fusion).

Two regulatory genes and four accessory genes complete the genome. Tat transactivates transcription, driving efficient elongation of viral RNA. Rev exports the unspliced and partially spliced viral mRNAs from the nucleus, switching the infection from its early to its late phase. Among the accessory proteins, Nef downregulates CD4 and major histocompatibility complex (MHC) class I and raises virion infectivity; Vif neutralises the host restriction factor APOBEC3G; Vpu (unique to HIV-1) counteracts the restriction factor tetherin (BST-2) and degrades CD4; and Vpr arrests the cell cycle and assists nuclear import. (HIV-2 and the SIVs carry Vpx in place of Vpu, which degrades the restriction factor SAMHD1.)

Replication cycle

HIV-1 is the prototypical Baltimore Group VI virus. Infection begins when gp120 engages CD4 on the target cell. This triggers a conformational change that lets gp120 bind a chemokine co-receptor, either CCR5 or CXCR4, which determines cellular tropism: R5 (CCR5-using) viruses predominate in transmission and early disease, while X4 (CXCR4-using) variants tend to emerge later and are associated with faster decline. People homozygous for the CCR5-Δ32 deletion lack the co-receptor and are largely resistant to R5 infection, the basis of the only documented cures. gp41 then drives fusion of the viral and cellular membranes, releasing the core into the cytoplasm.

Reverse transcriptase copies the RNA genome into double-stranded DNA, introducing on the order of one error per genome each cycle and so generating the quasispecies. The pre-integration complex is imported into the nucleus, where integrase splices the proviral DNA into host chromatin. From the integrated provirus, host RNA polymerase II transcribes viral RNA; Tat amplifies this enormously and Rev exports the unspliced transcripts. Gag and Gag-Pol polyproteins assemble at the plasma membrane, package two genomic RNA copies, and bud as immature particles; protease then cleaves the polyproteins to produce the mature, infectious virion with its conical core. An untreated person produces on the order of ten billion virions a day, with continuous cell-free and cell-to-cell spread.

The cell counters infection with intrinsic restriction factors: TRIM5α (targets the incoming capsid), APOBEC3G (hypermutates the genome unless degraded by Vif), tetherin / BST-2 (retains budding virions unless countered by Vpu), and SAMHD1 (depletes the deoxynucleoside triphosphate [dNTP] pool in non-dividing cells). Each of these the virus has evolved to evade. The combination of an error-prone RT, an enormous replicative output, and constant selection pressure is exactly why drug resistance arises so readily.

Reverse transcriptase, integrase, protease, the entry step (CCR5 antagonist maraviroc; fusion inhibitor enfuvirtide), and the capsid (lenacapavir) are all antiretroviral drug targets.

Pathogenesis

HIV preferentially infects activated CD4+ T cells, and also macrophages and central nervous system (CNS) microglia, which act as long-lived sources of virus. The earliest and most dramatic event is the massive depletion of CD4+ memory T cells in gut-associated lymphoid tissue during acute infection. The resulting damage to the mucosal barrier allows microbial products such as lipopolysaccharide to translocate into the circulation, and this, together with persistent viral antigen, drives the chronic immune activation that is now understood to be the engine of disease progression. Sustained activation produces lymphoid-tissue fibrosis, B-cell hyperactivation, exhaustion of T-cell responses, and the low-grade inflammation that underlies much of the non-AIDS cardiovascular, renal and neurocognitive morbidity seen even in treated infection.

The HIV envelope is one of the most sophisticated immune evaders in clinical virology. gp120 is cloaked in a dense glycan shield of host-derived N-linked sugars that hides conserved epitopes from antibody. Within each host, relentless sequence variation in the variable loops (V1 to V5) of gp120 outruns the maturing neutralising antibody response. CD8+ cytotoxic T cells bring down the acute viraemia and shape the set point, but escape mutants emerge under T cell pressure, and persistent antigen drives T cell exhaustion.

Untreated, the CD4 count falls by an average of 50 to 100 cells/µL per year, faster once X4 variants emerge. Crucially, even fully suppressive therapy does not eradicate the virus: a latent reservoir of integrated, replication-competent provirus in long-lived resting memory CD4+ T cells is established within days of infection, is maintained by the normal homeostatic proliferation of those cells, and reseeds active infection within two to three weeks of stopping treatment. Most of the persisting provirus is defective, but the small intact fraction is sufficient to rebound. This is why HIV is a lifelong infection and why cure remains so difficult.

Epidemiology

Around 39 million people are living with HIV worldwide (UNAIDS 2024), with around 1.3 million new infections and around 630,000 AIDS-related deaths per year. The pandemic is heavily concentrated in sub-Saharan Africa, which carries around two-thirds of the global burden. Eastern and southern Africa together account for more than half of all people living with HIV (PLHIV).

Both HIV-1 and HIV-2 belong to a wider family of simian immunodeficiency viruses (SIVs) that are widespread in non-human primates and largely non-pathogenic in their natural hosts. The host restriction factors (TRIM5α, APOBEC3G, tetherin and SAMHD1 among them) normally constitute a potent barrier to cross-species transmission, and the zoonotic events that gave rise to the four HIV-1 groups required the accumulation of viral mutations enabling escape from those factors. Passage through the chimpanzee appears to have been critical to the emergence of group M, the pandemic lineage.

Dissemination of HIV-1 from central western Africa during the twentieth century was facilitated by increased human-to-human contact through urbanisation, mass migration and a rising prevalence of sexually transmitted infections, particularly those causing genital ulceration, which disrupt the protective mucosa and increase per-act transmission efficiency. As group M spread, population bottleneck founder events established different lineages in different geographical regions; the modern subtype map is essentially a record of those founder histories.

The major migration pathways are now well characterised. Subtypes A and D originated in West Africa and went on to establish epidemics in eastern Africa, Russia and Central Asia. Subtype C was introduced to southern Africa and from there to India and parts of East Asia, and accounts for roughly half of all global infections. Subtype B, dominant in Europe and the Americas, arose from a single African strain that reached Haiti in the 1960s and spread from there to the United States and the wider Northern hemisphere. The CRF01_AE recombinant, which dominates the Southeast Asian epidemic, emerged in West Africa.

Transmission routes are sexual, both heterosexual and between men who have sex with men (MSM); vertical (mother-to-child, ante-, intra-, and post-partum through breastfeeding); and percutaneous (injecting drug use, transfusion of unscreened blood, occupational needlestick). Per-exposure transmission probabilities range from below 1 per 1,000 for sexual exposure (modified upward by viral load, genital ulceration, and uncircumcised status) to around 1 in 150 for needlestick exposure and around 25% for vertical transmission without prophylaxis.

Key populations at disproportionate risk include MSM, transgender women, sex workers, people who inject drugs (PWID), and people in prisons. In the South African and broader sub-Saharan African epidemic, adolescent girls and young women (AGYW) carry a disproportionate share of new infections.

Natural history

Untreated HIV infection passes through three phases.

Acute (primary) infection is marked by very high viraemia and dissemination of virus to lymphoid tissue. It is sub-divided serologically into the six Fiebig stages, from the first detectable RNA (stage I) to full antibody reactivity (stage VI), a framework used to time recent infection.

A partial immune response then brings the viral load down to a set point, and the patient enters clinical latency, a largely asymptomatic period lasting a median of about eight to ten years untreated, during which the CD4 count declines.

AIDS is defined by a CD4 count below 200 cells/µL or the occurrence of an AIDS-defining illness. Without therapy, progression from AIDS to death takes around two to three years, driven by opportunistic infections and malignancies.

A minority of people (long-term non-progressors and the rarer elite controllers) maintain CD4 counts and suppress viraemia for years without treatment, largely through favourable HLA-driven cellular immunity, the human leukocyte antigen (HLA) type shaping the strength of the cytotoxic T cell response.

Clinical presentations and complications

Acute retroviral syndrome

Acute retroviral syndrome occurs in many people two to four weeks after infection: an infectious-mononucleosis-like illness with fever, pharyngitis, a maculopapular rash, lymphadenopathy, myalgia, mucocutaneous ulceration and sometimes aseptic meningitis. It is easily mistaken for other viral illnesses; viraemia, and therefore infectiousness, is at its peak.

Clinical staging

The WHO clinical staging system (stages 1 to 4) is widely used alongside the CD4 count. Stage 1 is asymptomatic with generalised lymphadenopathy; stage 2 is minor mucocutaneous disease; stage 3 includes unexplained weight loss, persistent fever or diarrhoea, oral candidiasis, and pulmonary tuberculosis; stage 4 corresponds to AIDS-defining illness.

The CD4 count predicts which opportunistic infections become likely. Tuberculosis, herpes zoster and severe bacterial infection become common below about 350 cells/µL; Pneumocystis pneumonia, oesophageal candidiasis, cryptococcal disease and Kaposi sarcoma below 200; and disseminated Mycobacterium avium complex, cytomegalovirus (CMV) retinitis, cerebral toxoplasmosis and progressive multifocal leukoencephalopathy below 100.

Opportunistic infections and malignancies

Established disease presents through its complications. Tuberculosis is by far the most important worldwide; it occurs at any CD4 count and is the leading cause of death in people with HIV.

Other AIDS-defining conditions include:

• Pneumocystis jirovecii pneumonia (PJP).
• Cryptococcal meningitis (a major cause of mortality in advanced disease).
• Oesophageal candidiasis.
• Cerebral toxoplasmosis.
• CMV retinitis.
• Chronic cryptosporidial diarrhoea.
• Disseminated Mycobacterium avium complex.
• Progressive multifocal leukoencephalopathy (JC virus).

HIV also drives several virus-associated malignancies: Kaposi sarcoma (human herpesvirus 8, HHV-8), non-Hodgkin and CNS lymphoma (Epstein-Barr virus, EBV), and invasive cervical cancer (human papillomavirus, HPV).

Advanced HIV disease (a CD4 count below 200 cells/µL or a WHO stage 4 condition) warrants an intensified package of screening for, and prophylaxis against, the major opportunistic infections.

Non-AIDS complications in the ART era

In the era of effective ART, non-AIDS complications have become the dominant cause of morbidity and mortality in people with treated HIV. These include accelerated cardiovascular disease, chronic kidney disease, non-AIDS-defining malignancies, hepatic disease (hepatitis B virus [HBV] and hepatitis C virus [HCV] co-infection), neurocognitive impairment, and osteoporosis, all driven by residual chronic immune activation and the cumulative effects of long-term ART.

Diagnosis

Laboratory diagnosis follows a serial algorithm: a highly sensitive screening test, with every reactive result confirmed on a second, independent assay so that the combined positive predictive value exceeds the WHO threshold. The detectable markers appear in a fixed order after infection. There is first an eclipse period during which nothing is detectable; HIV RNA becomes detectable at around 10 to 11 days, the p24 antigen a few days later, IgM at about three weeks, and mature IgG over the following two to six weeks.

Assays are classified by generation. The fourth-generation antigen / antibody combination assay (detecting p24 antigen together with antibody, and closing the window to about two weeks) is the standard laboratory screening test; fifth-generation assays additionally report the antigen and antibody results separately and discriminate HIV-1 from HIV-2. Rapid point-of-care tests are antibody-based and have a slightly longer window. Screening is run either on a laboratory fourth-generation assay or through validated sequential rapid-test algorithms, always with confirmation on a second, independent assay.

Two situations require nucleic-acid testing rather than serology. Infants under 18 months carry transplacental maternal antibody, so diagnosis relies on HIV PCR (early infant diagnosis), not antibody tests. And a recent high-risk exposure within the diagnostic window may need RNA testing to detect infection before antibodies appear.

An increasingly important caveat is that long-acting injectable PrEP (cabotegravir or lenacapavir) can blunt antibody production and lower the viral load, producing delayed or atypical diagnostic patterns and a risk of undetected breakthrough infection, a pitfall to keep in mind as long-acting agents are rolled out. Quantitative viral load is the tool for monitoring the response to therapy and for defining virological failure.

Management

There is no cure, but combination antiretroviral therapy renders HIV a manageable chronic disease and, by suppressing viraemia, also prevents onward transmission. Standard therapy combines at least three active drugs, most often two nucleoside reverse transcriptase inhibitors with an integrase inhibitor.

First-line ART

The integrase inhibitor dolutegravir, paired with tenofovir and lamivudine or emtricitabine, has become the WHO-preferred first-line regimen in most of the world for its potency, tolerability and high barrier to resistance. Single-tablet formulations dominate clinical practice.

Antiretroviral drug classes

The major drug classes act at distinct points of the replication cycle:

• Nucleoside / nucleotide reverse transcriptase inhibitors (NRTIs): tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, emtricitabine, abacavir, zidovudine.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs): efavirenz, rilpivirine, doravirine, etravirine. (Inactive against HIV-2.)
• Integrase strand-transfer inhibitors (INSTIs): dolutegravir, bictegravir, raltegravir, cabotegravir.
• Protease inhibitors (PIs): darunavir / ritonavir, atazanavir / ritonavir, lopinavir / ritonavir.
• Entry inhibitors: CCR5 antagonist maraviroc; fusion inhibitor enfuvirtide; attachment inhibitor fostemsavir.
• Capsid inhibitor: lenacapavir (six-monthly subcutaneous injection).

Resistance and adherence

Because the error-prone reverse transcriptase throws up resistant variants whenever drug pressure is incomplete, adherence and viral-load monitoring are central to keeping a regimen working. Genotypic resistance testing on the polymerase gene (with integrase added selectively) guides switch decisions at virological failure.

Monitoring

Quantitative viral load at 3 to 6-monthly intervals is the primary monitoring tool. CD4 count is used at baseline for risk stratification but is no longer required for routine monitoring of patients with suppressed viral load.

Prevention and public health

Prevention is now highly effective and increasingly biomedical.

Vaccination

No vaccine has yet succeeded. The Thai RV144 trial remains the only one to show any efficacy (about 31%, not durable). The South African HVTN 702 / Uhambo trial, which adapted that approach to a subtype-C envelope, was stopped for futility in 2020; the Imbokodo and Mosaico mosaic-vaccine trials subsequently failed as well.

The obstacles are fundamental: extreme envelope diversity, the glycan shield, the absence of a clear correlate of protection, and the early establishment of the latent reservoir before immunity can act. A subset of people eventually develop broadly neutralising antibodies (bnAbs) targeting conserved sites such as the CD4-binding site, the membrane-proximal external region of gp41, and the V1V2 and V3-glycan supersites. These can prevent acquisition of sensitive strains in trials, but only a fraction of circulating viruses are susceptible to any one antibody, and bnAbs arise too late to help the person who makes them.

The same latent reservoir is why the only documented HIV cures (the Berlin, London, and a handful of similar patients) have required CCR5-Δ32 allogeneic stem-cell transplantation, a procedure far too toxic to scale. Current cure research instead pursues remission strategies combining latency-reversing agents, broadly neutralising antibodies, and immune-based therapies, with the goal of sustained ART-free viral control rather than complete eradication.

Infection prevention and control

Standard precautions for blood and body-fluid exposure prevent healthcare-associated HIV transmission. Safe injection practices, universal blood-donor screening, sterile surgical and dental instruments, and the use of personal protective equipment are foundational. Universal precautions have largely eliminated transfusion-transmitted HIV in countries with adequate blood services.

Post-exposure prophylaxis

Post-exposure prophylaxis (PEP) is a 28-day course of three antiretroviral drugs (typically tenofovir / emtricitabine plus dolutegravir) started within 72 hours of high-risk exposure (occupational needlestick, sexual exposure, sexual assault). Earlier initiation is more effective.

Treatment as prevention

Treatment as prevention is foundational. A person with a sustained viral load below 200 copies/mL does not transmit HIV sexually (the principle of U=U, “undetectable equals untransmittable”). This applies to all sexual transmission routes and has reshaped both clinical counselling and public-health strategy.

Pre-exposure prophylaxis (PrEP) is available as daily oral tenofovir / emtricitabine, as long-acting injectable cabotegravir (two-monthly), and (newest) as six-monthly lenacapavir, which showed striking efficacy in the PURPOSE trials. PrEP requires regular testing for HIV (to detect breakthrough infection and avoid mono-class antiretroviral exposure in undiagnosed infection), STIs, and (for tenofovir) renal function.

Voluntary medical male circumcision (VMMC) reduces female-to-male transmission by about 60% and remains a key intervention in high-burden settings.

Maternal viral suppression with antiretroviral therapy (prevention of vertical transmission, PMTCT) has driven mother-to-child transmission below the WHO elimination threshold (under 5%) in many countries.

Harm reduction

For people who inject drugs, needle and syringe programmes and opioid agonist therapy substantially reduce HIV transmission. Integration with HIV testing and ART is essential.

Surveillance and notification

HIV is globally notifiable. UNAIDS maintains the principal global surveillance dataset. National HIV programmes feed cascade-of-care indicators (95-95-95) to track elimination progress.

Outbreak response

While HIV is endemic rather than outbreak-driven in most settings, transmission cluster identification using molecular phylogenetics is increasingly used to prioritise prevention resources to active networks of onward transmission, particularly in MSM and PWID populations.

Elimination and eradication

UNAIDS targets aim to end AIDS as a public-health threat by 2030 through the 95-95-95 framework: 95% of PLHIV diagnosed, 95% of those diagnosed on ART, and 95% of those on ART with suppressed viral load. The three targets multiply: 95-95-95 corresponds to 86% of all PLHIV being virally suppressed, well above the threshold for epidemic control. The 2030 targets also include fewer than 370,000 new infections and fewer than 250,000 AIDS-related deaths per year globally.

South African context

South Africa carries the largest national HIV epidemic in the world, with around 7.7 million people living with HIV in 2024 (UNAIDS) and an adult HIV prevalence of around 13.9%. The epidemic is heavily generalised but with marked geographic, age, and key-population variation.

KwaZulu-Natal carries the highest provincial prevalence (around 18% in adults aged 15 to 49), followed by Mpumalanga, the Free State, the Eastern Cape, and Gauteng. The Western Cape and Northern Cape have the lowest provincial prevalence.

Adolescent girls and young women aged 15 to 24 carry a disproportionate share of new infections. MSM, sex workers, transgender people, and PWID are recognised key populations with targeted prevention and treatment programmes.

Almost all South African HIV-1 isolates are group M subtype C, which has shaped both the local epidemic biology and the regional vaccine and therapeutic development agenda.

South Africa runs the largest public ART programme in the world, with around 5.7 million people on ART in 2024. The 2023 National Department of Health (NDoH) Adult Antiretroviral Treatment Guideline sets out dolutegravir + tenofovir disoproxil fumarate + lamivudine or emtricitabine as the universal first-line regimen, with universal test-and-treat (start ART at diagnosis regardless of CD4) operative since 2016.

Progress toward 95-95-95 (UNAIDS 2024 estimates for South Africa):

• 94% of PLHIV diagnosed.
• 78% of those diagnosed on ART.
• 92% of those on ART virally suppressed.

The second indicator (linkage to ART) is the principal gap. The combined cascade corresponds to around 67% viral suppression of all PLHIV, short of the 86% target.

Oral PrEP has been progressively expanded in the public sector for AGYW, MSM, transgender people, sex workers, and serodiscordant couples since 2016. Long-acting cabotegravir PrEP and lenacapavir PrEP introduction is underway, with national-level scale-up prioritised for AGYW.

PMTCT scale-up has driven the vertical transmission rate below 1% at 10 weeks postpartum and to around 3% at 18 months, approaching the WHO elimination target.

HIV is not a Notifiable Medical Condition (NMC) in South Africa; it is managed through programmatic surveillance rather than case notification. AIDS-defining illnesses such as tuberculosis are notifiable in their own right.

HBV co-infection is common (genotype A1 dominant) and is covered by the tenofovir component of first-line ART. HCV co-infection is concentrated in PWID and MSM populations and requires direct-acting antiviral cure alongside HIV care.

References and recommended reading

• Bekker L-G, Beyrer C, Mgodi N, et al. HIV infection. Nat Rev Dis Primers 2023;9:42. DOI: 10.1038/s41572-023-00452-3.
• Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology, 4th ed. ASM Press; 2016. (Human immunodeficiency viruses, Chapter 34.)
• International Committee on Taxonomy of Viruses. 2024 taxonomy update for the family Retroviridae. Arch Virol 2025.
• South African National Department of Health. 2023 ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy and Breastfeeding, Adolescents, Children, Infants and Neonates. Pretoria: NDoH; 2023.
• UNAIDS. Global AIDS Update 2024: The Urgency of Now. Geneva: UNAIDS; 2024.