HIV

Subjects: virology, microbiology · Systems: virology, microbiology · Tags: virology, microbiology

Human Immunodeficiency Virus (HIV)

Human immunodeficiency virus (HIV) is a retrovirus belonging to the genus Lentivirus within the family Retroviridae. It is the causative agent of acquired immunodeficiency syndrome (AIDS), a condition characterized by progressive immune system failure and susceptibility to opportunistic infections and certain malignancies. Two major types infect humans: HIV-1, the predominant and globally widespread form, and HIV-2, largely restricted to West Africa and generally less transmissible and pathogenic.

Structurally, HIV is an enveloped, spherical virus about 100–120 nm in diameter. Its genome consists of two copies of single-stranded positive-sense RNA. Enclosed within the conical capsid made of p24 protein are the viral enzymes reverse transcriptase, integrase, and protease, all essential for replication. Surrounding the capsid is a matrix (p17) and a lipid envelope derived from the host cell membrane. Embedded in this envelope are the critical glycoproteins gp120 and gp41, which together form the Env spike. Gp120 mediates attachment to host receptors, while gp41 drives fusion of the viral and cellular membranes. This envelope glycoprotein is the main target of neutralizing antibodies, but its variability and shielding by glycans make it a difficult vaccine target.

The genome organization of HIV is compact but sophisticated. Beyond the structural genes (gag, pol, env), it encodes several accessory proteins that fine-tune replication and immune evasion. Tat is a transactivator that dramatically enhances viral transcription. Rev regulates the export of unspliced and partially spliced RNAs. Nef downregulates CD4 and MHC class I molecules, impairing T-cell function and immune recognition. Vif counteracts the host antiviral protein APOBEC3G, while Vpu antagonizes tetherin, a cellular restriction factor that prevents virion release. These accessory proteins explain HIV’s persistence and ability to replicate in the face of robust host defenses.

The replication cycle begins when gp120 binds to the primary receptor CD4, expressed on helper T lymphocytes, macrophages, and dendritic cells. This binding induces conformational changes allowing interaction with a co-receptor, either CCR5 or CXCR4. Viruses that use CCR5 dominate in early infection and are termed “R5-tropic,” while CXCR4-using (“X4-tropic”) viruses often emerge later in disease progression. After receptor engagement, gp41 mediates fusion of the viral and cellular membranes, releasing the viral core into the cytoplasm. Reverse transcriptase then converts the RNA genome into double-stranded DNA, a process prone to error, accounting for HIV’s high mutation rate. This viral DNA is transported to the nucleus and integrated into the host genome by integrase, establishing a provirus that can remain latent or be actively transcribed. Viral proteins are synthesized, assembled at the plasma membrane, and bud from the cell. During or after budding, protease cleaves precursor polyproteins into their functional forms, producing mature infectious virions.

The pathogenesis of HIV infection is defined by progressive depletion of CD4+ T cells and widespread immune dysfunction. Several mechanisms contribute to CD4 decline: direct viral cytopathic effect, induction of apoptosis, and immune-mediated killing of infected cells. Persistent immune activation, a hallmark of HIV disease, drives bystander T-cell depletion and immune exhaustion. The gut-associated lymphoid tissue (GALT) is a major early site of CD4 destruction, with rapid and often irreversible loss of mucosal immunity. Over years, the gradual decline in CD4 count predisposes to opportunistic infections, certain cancers such as Kaposi sarcoma and non-Hodgkin lymphoma, and wasting syndromes.

Clinically, HIV infection progresses through well-described stages. Acute HIV syndrome occurs 2–4 weeks after exposure, presenting with fever, pharyngitis, rash, lymphadenopathy, and malaise, often indistinguishable from mononucleosis or influenza. This phase corresponds to high-level viremia and widespread dissemination. A latent or chronic phase follows, during which viral replication continues in lymphoid tissue but symptoms may be minimal or absent. Without therapy, most individuals eventually progress to AIDS, defined by either a CD4 count below 200 cells/µL or the presence of AIDS-defining illnesses such as Pneumocystis jirovecii pneumonia, esophageal candidiasis, CMV retinitis, or disseminated Mycobacterium avium complex. The timeline from infection to AIDS varies but averages about 8–10 years without treatment.

The diagnosis of HIV infection relies on serologic and molecular testing. Screening begins with highly sensitive antigen/antibody combination immunoassays that detect both anti-HIV antibodies and the p24 antigen, allowing earlier detection during acute infection. Reactive results are confirmed with supplemental antibody differentiation assays. Nucleic acid testing (NAT) detects viral RNA and is used for confirmation, acute infection, and monitoring therapy. The CD4 count and plasma viral load are critical markers: CD4 count reflects immune status, while viral load reflects the intensity of replication and predicts disease progression and treatment response.

The treatment of HIV has been revolutionized by antiretroviral therapy (ART), which combines drugs from different classes to maximally suppress replication and prevent resistance. The main classes are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside RT inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and entry inhibitors including CCR5 antagonists and fusion inhibitors. Modern first-line regimens typically include two NRTIs plus an INSTI. When taken consistently, ART reduces viral load to undetectable levels, restores immune function, and prevents transmission, embodying the principle of “U=U” (undetectable equals untransmittable). Treatment is lifelong, as latent reservoirs of integrated provirus persist in resting memory CD4 cells, preventing cure.

From a public health and prevention perspective, HIV remains a major global challenge. Transmission occurs through sexual contact, blood exposure, and vertically from mother to child during pregnancy, delivery, or breastfeeding. Preventive strategies include barrier protection, harm reduction programs for intravenous drug use, and biomedical tools such as pre-exposure prophylaxis (PrEP) with daily oral NRTIs and post-exposure prophylaxis (PEP) after accidental exposure. Antenatal screening and maternal ART have dramatically reduced vertical transmission. Vaccine development remains elusive due to the virus’s diversity, glycan shielding of Env, and integration into host genomes.

For examination purposes, several high-yield points stand out. HIV is a retrovirus with reverse transcriptase, integrating as a provirus into host DNA. It specifically targets CD4+ T cells via gp120 binding to CD4 and CCR5/CXCR4 co-receptors. Key accessory proteins (Nef, Tat, Rev, Vif, Vpu) are crucial to its pathogenesis and immune evasion. The clinical progression follows a sequence of acute retroviral syndrome, latency, and eventual AIDS. Treatment with combination ART is highly effective but not curative, due to the persistence of latent reservoirs. Opportunistic infections define the late stage of disease, and understanding their association with CD4 count thresholds is fundamental for clinical reasoning.

Disclaimer: For education only. Not medical advice; always follow your institution's guidance.