HIV Infection and AIDS

The Virus

Retrovirus, Lentivirus genus. Enveloped, icosahedral, 2 copies (+)ssRNA + RT + integrase + protease.

HIV-1 (global pandemic, groups M/N/O/P, M=clades A-K) vs HIV-2 (West Africa, less transmissible, slower progression).

Envelope: gp120+gp41 (=gp160 precursor). Attachment: CD4 (primary receptor) + co-receptor:

• CCR5 (R5 strains, macrophage-tropic, early/transmitted infection)
• CXCR4 (X4 strains, T-cell-tropic, later disease, faster progression)

Tropism: CD4+ T helper cells, macrophages, dendritic cells, microglia.

Replication Cycle

Retroviral pattern (see General Virus Properties). Key step: REVERSE TRANSCRIPTION. Fusion (gp120/CD4/co-receptor) → RT converts (+)RNA → dsDNA (via RNA:DNA hybrid, RT’s RNA-dep-DNA-polymerase + RNase H activities) → nuclear transport → INTEGRATION (integrase) into host chromosome = PROVIRUS.

Provirus = permanent, establishes LIFELONG infection (latent, invisible to immunity/drugs). Active transcription → genomic RNA + mRNA → assembly/budding (plasma membrane) → immature virion → PROTEASE cleaves Gag-Pol → mature infectious virion (blocked by protease inhibitors).

Pathogenesis

Progressive CD4+ T cell depletion: direct cytopathic killing + immune-mediated killing + chronic immune activation/exhaustion. ↓CD4 → ↓CMI → opportunistic infections/malignancies.

Transmission: sexual (dominant global route), blood/needle-sharing, vertical (transplacental/intrapartum/breastfeeding).

Natural history (untreated):

1. Acute retroviral syndrome (2-4wk post-exposure): fever, LAD, rash, pharyngitis, mono-like illness + high viremia burst
2. Clinical latency (years): lower steady-state viral “set point,” largely asymptomatic, CD4 slowly declines
3. AIDS: CD4<200 OR AIDS-defining illness (whichever first)

Clinical Manifestations by CD4 Count

CD4>500: asymptomatic or acute retroviral syndrome only. CD4 200-500: bacterial infections (recurrent pneumonia, TB — TB occurs at ANY CD4 count unlike other opportunists), oral/vaginal candidiasis, herpes zoster, Kaposi sarcoma. CD4<200: Pneumocystis jirovecii pneumonia (PJP, CLASSIC AIDS-defining OI), cryptococcal meningitis, toxoplasma encephalitis. CD4<50: disseminated MAC (M. avium complex), CMV retinitis, PML (JC virus).

AIDS-defining malignancies: Kaposi sarcoma (HHV-8), non-Hodgkin lymphoma, invasive cervical cancer.

Laboratory Diagnosis

Screening: 4th-gen ELISA/rapid test — detects BOTH Ab + p24 antigen simultaneously. ↓window period (p24 appears before Ab).

Confirmation: 2nd different rapid test/ELISA (WHO/NACO strategy, different Ag/format) OR Western blot/line immunoassay (multiple specific band pattern).

Viral load (HIV RNA real-time PCR): baseline severity, treatment monitoring (suppressive ART → below detection limit), rebound = poor adherence or resistance.

CD4 count (flow cytometry): immunological status, OI prophylaxis threshold (cotrimoxazole typically <CD4 200), confirms immune reconstitution.

Early infant diagnosis: maternal Ab crosses placenta, persists up to 18mo in EXPOSED UNINFECTED infant → antibody test UNRELIABLE. Use HIV DNA/RNA PCR instead.

Treatment — ART (Antiretroviral Therapy)

Combination therapy (multiple classes) — monotherapy/incomplete regimen → rapid resistance (high mutation rate).

Standard first-line: 2 NRTIs (e.g. tenofovir+lamivudine) + 3rd agent from different class:

• INSTI (dolutegravir) — PREFERRED first-line (most guidelines incl. India)
• NNRTI (efavirenz)
• PI (boosted with ritonavir/cobicistat)

“Treat all” — ART for EVERYONE diagnosed, regardless of CD4 count. Basis: preserves immunity + prevents transmission = U=U (undetectable=untransmittable).

PMTCT: maternal ART throughout pregnancy+breastfeeding + infant prophylaxis + formula feeding (if feasible) → transmission risk 25-30%(untreated) → <2%.

PrEP: daily oral tenofovir-based, HIV-negative high-risk individuals, highly effective if consistent. PEP: 28-day ART course, ASAP (ideal <2hr, ineffective >72hr) post high-risk exposure — see Needle Stick Injury topic.

Prevention

Biomedical: ART/U=U, PrEP, PEP, PMTCT. Behavioral: safe sex (condoms, partner reduction), blood-supply screening, safe injection practices (needle exchange, no sharing), public health education. NO VACCINE currently exists.

The Virus

Human immunodeficiency virus (HIV) is a retrovirus of the Lentivirus genus — an enveloped, icosahedral virion carrying two identical copies of positive-sense single-stranded RNA, plus its own reverse transcriptase, integrase, and protease enzymes. Two species infect humans: HIV-1 (the dominant global pandemic strain, itself split into groups M, N, O, P, with group M further split into clades/subtypes A through K) and HIV-2 (largely confined to West Africa, less transmissible and more slowly progressive).

The envelope carries two key glycoproteins, gp120 and gp41 (together forming the gp160 precursor spike), which mediate attachment and entry. Attachment requires CD4 as the primary receptor plus a co-receptor — CCR5 (used by macrophage-tropic, R5 strains, dominant in early/transmitted infection) or CXCR4 (used by T-cell-tropic, X4 strains, which tend to emerge later in disease and correlate with faster progression). This receptor requirement explains HIV’s cellular tropism directly: CD4+ T helper cells, macrophages, dendritic cells, and microglia are all natural targets.

Replication Cycle

HIV replication follows the retroviral pattern in detail (see General Properties of Viruses for the general steps), with the defining feature being reverse transcription: after gp120/CD4/co-receptor-mediated fusion releases the nucleocapsid into the cytoplasm, reverse transcriptase converts the genomic RNA into double-stranded proviral DNA (via an RNA:DNA hybrid intermediate, using both its RNA-dependent DNA polymerase and ribonuclease H activities). This proviral DNA is transported into the nucleus and permanently integrated into the host chromosome by viral integrase — the step that establishes lifelong infection, since the provirus becomes a stable part of the host cell’s own genome, invisible to immune surveillance and antiretroviral drugs alike while latent. Active transcription from the integrated provirus produces new genomic RNA and mRNA for viral proteins; assembly and budding at the plasma membrane release new, initially immature virions, which mature into infectious particles once viral protease cleaves the Gag-Pol polyprotein into its functional components — the step blocked by protease inhibitors.

Pathogenesis

HIV’s defining pathogenic feature is progressive depletion of CD4+ T cells, through direct viral cytopathic killing, immune-mediated killing of infected cells, and chronic immune activation that drives T-cell exhaustion and turnover. As CD4 counts fall, cell-mediated immunity progressively collapses, opening the door to opportunistic infections and malignancies that a competent immune system would normally suppress.

Transmission occurs through sexual contact (the dominant global route), blood/blood products and shared needles, and vertical transmission (transplacental, intrapartum, or via breastfeeding).

Natural history without treatment runs through recognizable stages: an acute retroviral syndrome (2–4 weeks post-exposure — fever, lymphadenopathy, rash, pharyngitis, a mononucleosis-like illness, coinciding with a burst of high-level viraemia before the immune response partially controls it); a clinical latency period (years, during which the virus continues replicating at a lower steady-state level — the “set point” — largely asymptomatically, while CD4 counts slowly decline); and progression to AIDS, defined by a CD4 count <200 cells/μL or the occurrence of an AIDS-defining illness, whichever comes first.

Clinical Manifestations and Opportunistic Infections

Disease manifestations track CD4 count closely, which is why CD4 count (alongside viral load) drives clinical staging and prophylaxis decisions:

• CD4 >500: often asymptomatic or acute retroviral syndrome only.
• CD4 200–500: bacterial infections (recurrent pneumonia, TB — notably, TB can occur at any CD4 count, unlike most other opportunists), oral/vaginal candidiasis, herpes zoster, Kaposi sarcoma.
• CD4 <200: Pneumocystis jirovecii pneumonia (PJP, the classic AIDS-defining opportunistic infection), cryptococcal meningitis, toxoplasma encephalitis.
• CD4 <50: disseminated Mycobacterium avium complex (MAC), CMV retinitis, and progressive multifocal leukoencephalopathy (JC virus).

AIDS-defining malignancies: Kaposi sarcoma (driven by co-infection with HHV-8), non-Hodgkin lymphoma, invasive cervical cancer.

Laboratory Diagnosis

Screening: fourth-generation ELISA/rapid tests detecting both HIV antibody and p24 antigen simultaneously — this combination shortens the diagnostic window period (the interval after infection before a test turns positive) compared with antibody-only assays, since p24 antigen appears in blood before antibody does.

Confirmation: a reactive screening test is confirmed either by a second, different rapid test/ELISA (per WHO/NACO strategy, using tests targeting different antigens/formats to build confidence without needing Western blot) or, in settings that still use it, by Western blot or a line immunoassay demonstrating antibody bands against multiple specific viral proteins.

Viral load (HIV RNA by real-time PCR) is central to monitoring: it establishes baseline severity, is repeated periodically to confirm treatment response (a properly suppressive antiretroviral regimen should drive viral load to below the assay’s detection limit), and a rebound signals either poor adherence or emerging drug resistance.

CD4 count (flow cytometry) tracks immunological status directly, guiding opportunistic-infection prophylaxis thresholds (e.g. cotrimoxazole prophylaxis against PJP typically starts below CD4 200) and confirming immune reconstitution on treatment.

Early infant diagnosis: since maternal antibody crosses the placenta and persists in an exposed but uninfected infant for up to 18 months, antibody-based testing is unreliable in this age group — HIV DNA/RNA PCR is required instead to diagnose infection in infants born to HIV-positive mothers.

Treatment: Antiretroviral Therapy (ART)

Modern management is combination antiretroviral therapy (ART), using drugs from multiple classes together to suppress replication durably and prevent resistance — monotherapy or incomplete regimens select resistant virus rapidly, given HIV’s high mutation rate. Standard first-line regimens combine two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs, e.g. tenofovir + lamivudine) with a third agent from a different class — an integrase strand transfer inhibitor (dolutegravir, now preferred first-line in most guidelines including India’s), a non-nucleoside reverse transcriptase inhibitor (efavirenz), or a protease inhibitor (boosted with ritonavir/cobicistat).

ART is now recommended for everyone diagnosed with HIV, regardless of CD4 count (“treat all”), since durable viral suppression both preserves the individual’s immune function and prevents onward transmission — the basis of the “undetectable = untransmittable” (U=U) principle.

Prevention of mother-to-child transmission (PMTCT): maternal ART throughout pregnancy and breastfeeding, combined with infant prophylaxis and, where feasible, formula feeding, reduces transmission risk from ~25–30% untreated to under 2%.

Pre-exposure prophylaxis (PrEP): daily oral tenofovir-based regimens for HIV-negative individuals at substantial ongoing risk, highly effective when taken consistently. Post-exposure prophylaxis (PEP): a 28-day antiretroviral course started as soon as possible (ideally within 2 hours, generally considered ineffective beyond 72 hours) after a high-risk exposure — covered in more procedural detail under Needle Stick Injury and Standard Precautions.

Prevention

Beyond biomedical prevention (ART/U=U, PrEP, PEP, PMTCT), prevention rests on safe sexual practices (condom use, partner reduction), blood-supply screening, safe injection practices (needle exchange programmes, avoiding needle sharing), and broad public health education. No protective vaccine currently exists, despite decades of research effort.

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