HIV-1 — Questions

HIV crosses the blood-brain barrier chiefly within infected monocytes and macrophages, a “Trojan horse” mechanism, seeding perivascular macrophages and microglia as the productively infected brain cells.

Neurons lack CD4 and are not productively infected; their injury is indirect, via inflammatory mediators. The remaining routes (axonal transport, passive diffusion, endothelial infection) do not describe HIV neuroinvasion.

Broadly neutralising antibodies (bNAbs) neutralise a wide range of HIV-1 strains across subtypes. They develop in only a minority of infected people, and only after years, requiring extensive somatic hypermutation driven by prolonged exposure to a diversifying virus. They arise too late to control the infection in the person who makes them, but they define the conserved targets a vaccine must hit.

Targets. bNAbs recognise the small number of relatively conserved sites on the envelope trimer:

• the CD4-binding site (e.g. VRC01, 3BNC117);
• the V1/V2 apex (e.g. PG9, PG16);
• the V3-glycan supersite (e.g. PGT121, 2G12);
• the gp41 membrane-proximal external region (MPER) (e.g. 10E8, 4E10);
• the gp120–gp41 interface and the fusion peptide.

Why they are hard to elicit. The envelope defends these sites with a dense glycan shield of host sugars, conformational masking, hypervariable loops and sequence diversity, and the need for unusual, highly mutated antibody lineages. No immunogen has yet reliably induced bNAbs by vaccination.

Applications. bNAbs are being developed for prevention (the Antibody Mediated Prevention [AMP] trials showed VRC01 reduced acquisition of sensitive strains but not overall, showing that single antibodies are too narrow, so combinations or engineered multispecific antibodies are needed), for long-acting therapy, and as part of cure strategies, where they may both neutralise virus and recruit immune effectors to clear reservoir cells.

The gut-associated lymphoid tissue (GALT) holds most of the body’s CD4+ T cells, the majority of them activated, memory-phenotype, CCR5-expressing cells that are the ideal target for HIV. The GALT is therefore the site of the earliest and most massive CD4 depletion in infection: a large fraction of mucosal CD4+ T cells is destroyed within the first weeks, far exceeding the loss measurable in peripheral blood, and this depletion is only partially reversed by antiretroviral therapy.

The consequence is loss of mucosal immune integrity and breakdown of the epithelial barrier, letting microbial products (notably lipopolysaccharide) translocate from the gut lumen into the systemic circulation. This sustained antigenic stimulation is a major driver of the chronic immune activation that underlies disease progression and much of the non-AIDS morbidity (cardiovascular, neurocognitive) seen even in treated infection. The GALT is thus both an early casualty of HIV and an engine of its pathogenesis.

The latent reservoir is the population of cells carrying integrated, transcriptionally silent but replication-competent provirus, from which infection rebounds if therapy stops. It is the central obstacle to curing HIV.

What and where. The best-characterised reservoir is the long-lived resting memory CD4+ T cell (central, transitional and effector memory subsets), but provirus also persists in tissue macrophages and in sanctuary sites such as lymphoid tissue and the central nervous system. It is established within days of infection, before therapy can realistically begin, which is why even very early ART does not prevent it.

Why it persists. Once integrated, the silent provirus is invisible to the immune system and unaffected by antiretrovirals (which block new infection, not established proviral DNA). The reservoir is maintained by the normal homeostatic proliferation and antigen-driven clonal expansion of the memory T cells that harbour it, so it is remarkably stable over decades.

Intact versus defective. The great majority of persisting proviruses are defective (hypermutated or deleted) and cannot rebound; only a small intact fraction is rebound-competent. Measuring the clinically relevant reservoir is therefore difficult: the quantitative viral outgrowth assay and the intact proviral DNA assay attempt to quantify the replication-competent pool, while total proviral DNA overestimates it.

Clinical consequence. Stopping suppressive ART is followed by viral rebound within about two to three weeks, confirming lifelong infection. Cure research targets the reservoir directly: latency reversal (“shock and kill”), latency-promoting “block and lock”, broadly neutralising antibodies, and gene therapy.

HIV-associated nephropathy (HIVAN) is the classic direct renal disease of HIV, histologically a collapsing focal segmental glomerulosclerosis (FSGS) with microcystic tubular dilatation. Its pathogenesis is a two-hit process: direct viral injury to the renal epithelium acting on a genetically susceptible kidney, neither hit sufficient alone.

The viral hit. The kidney acts as an HIV reservoir: podocytes and tubular epithelial cells harbour virus and express viral genes, even though they are not productively infected in the usual CD4/CCR5-dependent way. Local expression of nef and vpr drives the injury:

• nef activates Src-family kinase and MAPK (mitogen-activated protein kinase) signalling, driving the normally growth-arrested podocyte to dedifferentiate and proliferate; this dysregulated proliferation collapses the glomerular tuft, the defining lesion.
• vpr causes apoptosis and G2 cell-cycle arrest, injuring podocytes and tubular epithelial cells; the tubular injury produces the microcysts.

The host hit. HIVAN occurs overwhelmingly in people of African ancestry, because of high-risk APOL1 variants (G1 and G2). The risk is recessive: two risk alleles are needed, and they sensitise the podocyte to injury. This genetic architecture is why HIVAN is a major cause of chronic kidney disease in the South African and broader sub-Saharan epidemic.

The interaction. Most people carrying two APOL1 risk alleles never develop HIVAN, and the virus rarely causes it without that susceptibility. Uncontrolled viraemia is the trigger, so HIVAN clusters in advanced, untreated infection (low CD4, high viral load), and antiretroviral suppression can reverse early disease, confirming the causal role of active viral gene expression.

A functional cure (better termed sustained virological remission) means durable, ART-free control of HIV: an undetectable viral load with no disease progression, without eradicating the virus. The latent reservoir persists but replication stays controlled. It contrasts with a sterilising cure, in which replication-competent virus is eliminated entirely, as in the Berlin and London patients after CCR5-Δ32 allogeneic stem-cell transplantation. Those cases are proof of concept that lifelong ART-free control is achievable, but the procedure is far too toxic to be a scalable cure.

Two approaches to functional cure have experimental support:

• Very early ART producing post-treatment control. In the VISCONTI cohort, a subset of people treated during acute infection maintained viral control for years after stopping therapy, attributed to a smaller, less diverse reservoir seeded before wide dissemination.
• Broadly neutralising antibodies (bNAbs). Combination bNAb infusion (for example 3BNC117 with 10-1074) has maintained ART-free suppression through analytical treatment interruption in a subset of people, and may also help clear reservoir cells by recruiting immune effectors.

Other reservoir-directed strategies under investigation include latency reversal (“shock and kill”), latency-promoting “block and lock”, and gene editing of CCR5.

A fourth-generation assay detects both p24 antigen and HIV antibody, shortening the window to about two weeks after infection, earlier than antibody-only tests because p24 antigenaemia precedes seroconversion. (Markers appear in order: HIV RNA at roughly 10 to 11 days, then p24 antigen, then IgM at about three weeks, then mature IgG over two to six weeks.)

A negative fourth-generation result during the window does not exclude HIV infection. During the preceding eclipse period no marker is detectable, and in the days around it a person may be infected, and highly infectious, yet test negative.

Clinically, therefore:

• If there has been a recent high-risk exposure, repeat testing after the window (commonly at four to six weeks, with a final test per the local algorithm), or test HIV RNA (nucleic acid) to detect infection earlier.
• Counsel that a negative test within the window is not reassuring, and advise precautions against onward transmission meanwhile.
• If the exposure was within 72 hours, consider post-exposure prophylaxis (PEP) rather than waiting to retest.
• Long-acting injectable pre-exposure prophylaxis (PrEP), such as cabotegravir, can blunt and delay both antigenaemia and the antibody response, prolonging the effective window and risking a missed or late diagnosis.

A small minority of untreated people deviate from the usual course of progressive CD4 decline. Long-term non-progressors stay clinically well with preserved CD4 counts for many years (often more than 7 to 10 years) despite detectable viraemia. Elite controllers, rarer still (well under 1%), spontaneously suppress viraemia below the limit of detection (under 50 copies/mL) off all therapy; viraemic controllers hold a low but detectable load (under about 2,000 copies/mL). The atypical course is multifactorial, with viral, host-genetic and immunological contributions.

Viral factors. A few controllers carry replication-defective or attenuated virus. In the Sydney Blood Bank Cohort a nef-deleted strain produced slow progression in the donor and recipients, establishing nef as a virulence factor. Escape mutations in conserved Gag epitopes that carry a fitness cost also slow replication. In most controllers, though, the virus is fully pathogenic and the explanation lies with the host.

Host genetic factors. Protective HLA class I alleles (B*57:03, B*81:01 and B*27) present conserved Gag epitopes and drive highly effective CD8 cytotoxic T-cell (CTL) responses, the strongest known genetic correlate of control. Heterozygosity for CCR5-Δ32 lowers co-receptor density and slows progression, while homozygosity gives near-complete resistance to CCR5-tropic virus. Certain killer-cell immunoglobulin-like receptor (KIR) genotypes, such as KIR3DS1/3DL1 with their HLA-Bw4 ligands, strengthen natural-killer-cell control.

Immunological factors. Control tracks with polyfunctional, high-avidity CD8 CTL responses against conserved Gag, preserved HIV-specific CD4 helper responses, and lower generalised immune activation with better-preserved lymph-node architecture, the opposite of the chronic activation that drives typical progression.

Control is not cure. Even elite controllers keep a latent reservoir, show low-level replication and residual inflammation, carry excess cardiovascular and other non-AIDS morbidity, and a proportion eventually lose control. The phenomenon still guides vaccine and cure research, since it shows that durable immune control of HIV is biologically possible.

Entry requires CD4 plus a chemokine co-receptor: CCR5 (R5 viruses) or CXCR4 (X4 viruses).

R5 viruses dominate transmission and early disease while X4 viruses tend to emerge later, and dual-tropic strains use either; this is the step blocked by the CCR5 antagonist maraviroc. DC-SIGN (dendritic-cell-specific ICAM-3-grabbing non-integrin) captures virus but is not the entry co-receptor, and CD8 and CD3 are unrelated T-cell markers.

AIDS is defined by a CD4 count below 200 cells/µL or by an AIDS-defining condition.

Specific opportunistic infections cluster at lower counts: Pneumocystis pneumonia around 200, and cryptococcal disease, cytomegalovirus (CMV) retinitis and disseminated Mycobacterium avium complex (MAC) below about 100.

Gag is cleaved into the structural proteins: matrix (p17), capsid (p24), nucleocapsid (p7) and p6.

The pol gene encodes the enzymes (protease, reverse transcriptase, integrase) and env encodes gp120 and gp41; Tat, Rev, Nef, Vif, Vpr and Vpu are regulatory and accessory proteins from other reading frames.

Dolutegravir is an integrase strand-transfer inhibitor (INSTI), blocking insertion of proviral DNA into host chromatin.

Its high potency, good tolerability and high genetic barrier to resistance make it the preferred first-line anchor drug. The distractors name steps handled by other drug classes: reverse transcriptase, protease, fusion and capsid inhibitors.

Error-prone reverse transcription, combined with an enormous replicative output (on the order of ten billion virions a day), generates a quasispecies, a swarm of related variants within each host.

This standing diversity is the raw material for immune escape and for the rapid selection of drug resistance, so the distractors (uniformity, reduced mutation, or loss of core functions) are the opposite of what high error rates produce.

HIV-2 derives from the sooty mangabey virus SIVsm (simian immunodeficiency virus of the sooty mangabey).

It shares only about 50 to 60% of its sequence with HIV-1, which arose separately from chimpanzee and gorilla lineages, and it is less transmissible and slower to progress.

Without a functional CCR5 co-receptor, R5 virus cannot enter, conferring near-complete resistance to infection.

This is the basis of the CCR5-Δ32 allogeneic stem-cell-transplant cures; CXCR4-using (X4) virus could in principle still enter, and heterozygotes are partially protected and progress more slowly. The distractors invert the phenotype or attach it to the wrong target.

Lenacapavir is the first-in-class capsid inhibitor, disrupting capsid function at uncoating, nuclear import and assembly.

Its very long half-life allows six-monthly subcutaneous dosing for both treatment and prevention. The distractors name the established, older drug-target classes.

Both target reverse transcriptase (RT), by different mechanisms.

Tenofovir is a nucleotide RT inhibitor, a chain-terminating analogue, whereas efavirenz is a non-nucleoside RT inhibitor acting allosterically. The distractors name other drug-target enzymes and structures.

Vpu (unique to HIV-1) antagonises tetherin (BST-2), which would otherwise hold budding virions at the cell surface; it also degrades CD4.

Vif counters APOBEC3G, and the HIV-2 and SIV protein Vpx counters SAMHD1; TRIM5α and MxA are restriction factors Vpu does not target.

The trimeric envelope spike is made of gp120 (surface, binds CD4) and gp41 (transmembrane, drives fusion).

Both are cleaved from the gp160 precursor, which is not itself the mature spike. The other options name internal structural proteins, enzymes, or influenza glycoproteins.

HIV is diploid, carrying two identical copies of positive-sense single-stranded RNA (about 9.7 kb each), flanked by long terminal repeats.

After entry, reverse transcriptase copies the RNA into double-stranded DNA. The distractors describe other virus classes: a DNA genome, a single negative-sense strand, a segmented orthomyxovirus genome, or the partially double-stranded circular DNA of hepatitis B.

The pol gene encodes protease, reverse transcriptase and integrase.

These are targeted respectively by the protease inhibitors, the nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, and the integrase strand-transfer inhibitors. The distractors mix in enzymes HIV does not encode, such as neuraminidase, helicase and thymidine kinase.

HIV-1 group M, the pandemic lineage, arose from chimpanzee SIVcpz (simian immunodeficiency virus of the chimpanzee).

Group N also came from SIVcpz, groups O and P from gorilla SIVgor, and HIV-2 (a separate virus) from sooty mangabey SIVsm.

HIV-1 is a retrovirus (family Retroviridae, genus Lentivirus), Baltimore Group VI: single-stranded RNA viruses that reverse-transcribe into DNA.

Group VII holds the DNA viruses that reverse-transcribe (hepatitis B), the common distractor, so option E pairs the right family with the wrong group. The remaining families and groups belong to unrelated viruses.

APOBEC3G is a host cytidine deaminase causing lethal G-to-A hypermutation of nascent viral DNA; HIV-1 Vif targets it for proteasomal degradation.

Option D describes tetherin countered by Vpu, and option E describes SAMHD1 countered by Vpx; the others pair invented functions with the wrong antagonist.

HIV-2 is naturally resistant to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and to enfuvirtide.

Some protease inhibitors are also less active against it, but it responds to nucleoside analogues and integrase inhibitors, so it is neither pan-susceptible nor restricted to a single class. The regimen and the viral-load assay both need choosing with HIV-2 in mind, since many HIV-1 assays miss it.

Subtype C predominates in southern Africa and India and accounts for roughly half of all infections globally.

Subtype B dominates Europe and the Americas, and the recombinant CRF01_AE dominates South-East Asia.

Rev binds the Rev-response element (RRE) and exports unspliced and partially spliced transcripts, switching the infection to its late phase.

Tat is the transcriptional transactivator; Nef, Vif and Vpr are accessory proteins with unrelated roles.

HIV RNA is detectable first, from about 10 to 11 days, so nucleic-acid testing closes the window earliest.

The markers then appear in order: p24 antigen, IgM at about three weeks, and mature IgG at two to six weeks; fourth-generation assays (p24 plus antibody) detect at about two weeks. A falling CD4 count is a downstream consequence, not an early diagnostic marker.

Transplacental maternal IgG persists in the infant for up to about 18 months, so a reactive antibody test may simply reflect maternal antibody rather than infant infection.

Early infant diagnosis therefore relies on HIV nucleic-acid testing by polymerase chain reaction (PCR); serology becomes interpretable from around 18 months. The distractors describe phenomena that do not occur.

Interpretation. A single detectable viral load of 50 to 199 copies/mL after sustained suppression is a viral blip: a transient result that returns to undetectable on repeat. Blips occur in ~10 to 30% of long-term suppressed patients and reflect stochastic release from the latent reservoir, intercurrent infection or vaccination, or assay variability near the detection limit. A single blip is not evidence of virological failure or drug resistance.

Action.

• Repeat the viral load (at the next routine visit, or in 4 to 6 weeks if pregnant or breastfeeding) and continue the current regimen unchanged.
• Do not request resistance testing on a single result below 1,000 copies/mL: genotyping needs a viral load above 1,000 copies/mL, and this does not meet the South African resistance-testing criteria.
• Reinforce adherence and counsel without alarm: the regimen is working and the repeat is almost always undetectable.

If the repeat is also detectable (50 to 999 copies/mL), the pattern is persistent low-level viraemia, which warrants intensified adherence support and a lower threshold for resistance testing. Sustained results at or above 1,000 copies/mL, after at least 9 months on a dolutegravir-based regimen with documented adherence support, define virological failure.

HIV is transmitted by three principal routes:

• Sexual: the dominant route worldwide, and overwhelmingly heterosexual in the sub-Saharan African epidemic. Receptive anal intercourse carries the highest per-act risk; vaginal, insertive and oral exposures follow.
• Parenteral (blood-borne): sharing of injecting equipment, occupational needlestick injury (~0.3% per percutaneous exposure to infected blood), and transfusion of infected blood or products (now rare where donations are screened).
• Vertical (mother-to-child): in utero, intrapartum, and through breastfeeding, the route targeted by prevention-of-mother-to-child-transmission programmes.

Per-exposure risk is raised by a high plasma viral load (hence the danger of acute infection), genital ulcers or other sexually transmitted infections, and the absence of male circumcision. Conversely, a person with a sustained viral load below 200 copies/mL does not transmit HIV sexually, the basis of treatment as prevention.