Describe HIV with its structure, replication, transmission, natural history and laboratory diagnosis.

Structure and Genome

• A retrovirus of the lentivirus genus — enveloped, with two identical copies of single-stranded positive-sense RNA (hence "diploid"), and a characteristic cone-shaped core
• Envelope glycoproteins — gp120, which binds the receptor, and gp41, which mediates fusion; both derive from gp160
• Core proteins — p24 (capsid, the antigen detected in fourth-generation tests) and p17 (matrix)
• Three virion enzymes — reverse transcriptase, integrase and protease; all three are drug targets
• Structural genes — gag (core proteins), pol (enzymes) and env (envelope); with regulatory genes tat, rev, nef, vif, vpr and vpu
• HIV-1 is worldwide and predominates in India; HIV-2 is largely confined to West Africa, is less transmissible, less virulent and slower to progress, and is intrinsically resistant to NNRTIs, which matters for treatment choice

Replication

Gp120 binds CD4 on the T helper lymphocyte, and also on macrophages, monocytes, dendritic and microglial cells → A conformational change exposes the CO-receptor binding site — CCR5 (macrophage-tropic strains, which dominate early) or CXCR4 (T-tropic strains, appearing later and heralding progression) → gp41 mediates fusion of the envelope with the cell membrane; the core enters → reverse transcriptase copies the RNA into double-stranded DNA. It has NO proofreading, so it makes about one error per genome per cycle — the origin of the enormous variability and of drug resistance → integrase inserts the DNA into the host chromosome as a provirus → The provirus may remain latent for years in resting memory T cells — the reservoir that makes cure impossible with current drugs → On activation, transcription and translation produce polyproteins; protease cleaves them during and after budding to yield the mature infectious virion

Transmission and Natural History

• Sexual transmission is much the commonest route worldwide and in India; risk is increased by genital ulceration, other sexually transmitted infections, and a high viral load in the source
• Blood-borne — transfusion (now rare with screening), shared needles among injecting drug users, needlestick injury (risk about 0.3%, far lower than hepatitis B), and unsterile procedures
• Vertical (mother to child) — in utero, at delivery (the largest component), and through breastfeeding; without intervention the risk is 20 to 45%, and with full prophylaxis it falls below 2%
• Not transmitted by casual contact, sharing utensils, insects, or ordinary social contact — a point that must be stated explicitly, since misunderstanding drives stigma

• Opportunistic infections track the CD4 count — below 200: Pneumocystis jirovecii pneumonia, oesophageal candidiasis; below 100: cerebral toxoplasmosis, cryptococcal meningitis; below 50: CMV retinitis and disseminated Mycobacterium avium complex. tuberculosis occurs at any CD4 count and is the commonest opportunistic infection and cause of death in India
• AIDS-defining malignancies — Kaposi sarcoma (HHV-8), non-Hodgkin and primary CNS lymphoma (EBV), and invasive cervical carcinoma (HPV)

Laboratory Diagnosis

• Fourth-generation ELISA detects p24 antigen together with antibody, shortening the window period to about 2 to 3 weeks from the 6 to 12 weeks of antibody-only tests
• India's national testing algorithm requires reactivity on three different rapid tests or ELISAs using different antigens or principles before HIV infection is reported; Western blot has largely been abandoned as costly and prone to indeterminate results
• Viral load by RT-PCR — used to monitor treatment (the aim is undetectable), to diagnose acute infection before seroconversion, and for infant diagnosis
• Infant diagnosis requires DNA PCR, not antibody, because maternal IgG crosses the placenta and persists for up to 18 months; testing is done at 6 weeks and thereafter under India's early infant diagnosis programme
• CD4 count by flow cytometry — staging, assessing risk of opportunistic infection, and deciding on prophylaxis
• Pre- and post-test counselling and confidentiality are mandatory; the HIV/AIDS Act 2017 in India prohibits discrimination and mandates informed consent for testing

Treatment and Prevention

• Antiretroviral therapy for all, regardless of CD4 count — "treat all" is now national and international policy. India's first-line regimen is TLD: tenofovir, lamivudine and dolutegravir, provided free through the National AIDS Control Programme
• U = U ("Undetectable = Untransmittable") — a person with a sustained undetectable viral load does not transmit HIV sexually. This is among the most important messages in HIV medicine, transforming both prevention and the experience of living with the diagnosis
• PMTCT — antenatal testing, antiretroviral therapy for the mother, prophylaxis for the infant, and safe infant feeding; this has reduced vertical transmission dramatically
• Post-exposure prophylaxis (PEP) — started within hours of a needlestick or other exposure and continued for 28 days; and pre-exposure prophylaxis (PrEP) for those at substantial ongoing risk
• Adherence determines resistance — intermittent treatment selects resistant virus rapidly, so adherence support is as important as the choice of drugs

Opportunistic Infections and Their Prevention

• Immune reconstitution inflammatory syndrome (iris) — paradoxical worsening of an existing infection as immunity recovers after starting antiretroviral therapy. It is not treatment failure; both treatments are continued and corticosteroids given where severe

Applied Aspects

• Screen every HIV patient for tuberculosis at every visit using the four-symptom screen, and test every tuberculosis patient for HIV; give co-trimoxazole prophylaxis at low CD4 counts
• Stigma remains the largest obstacle in India, deterring testing, disclosure and adherence; confidentiality, non-judgemental care and correct information about how HIV is not transmitted are as much a part of treatment as the drugs
• Test infants by PCR, never by antibody, until 18 months of age
• Start PEP within hours, not days, after a significant exposure; its effectiveness falls with delay, and the first dose should not await formal counselling
• Zoster, oral candidiasis or tuberculosis in a young adult should prompt HIV testing, since these are common presentations of undiagnosed infection
• Universal precautions protect against HIV and hepatitis together, and are applied to every patient rather than to those known to be infected — which is the entire point of the word "universal"
• Do not test for HIV without consent and counselling; this is a legal requirement in India under the HIV/AIDS Act, and disclosure without consent has caused documented harm
• Recognise iris and continue both treatments; apparent deterioration after starting antiretroviral therapy is usually immune recovery rather than failure
• A negative test in the window period is not reassurance after a high-risk exposure; repeat testing is required, and this must be explained at the first visit
• Ask about the CD4 count before interpreting a presentation; the same symptom means different things at 500 and at 50, and the differential diagnosis follows directly from the count
• Treat the opportunistic infection first in cryptococcal and tuberculous meningitis, and delay antiretroviral therapy for a few weeks, because iris in the central nervous system can be fatal
• Adherence is the whole of long-term success; resistance follows intermittent treatment far more readily than continuous treatment, so support, counselling and free supply matter as much as drug choice