Retroviruses are a family of enveloped RNA viruses characterized by their unique replication strategy: conversion of their RNA genome into double-stranded DNA by the enzyme reverse transcriptase, followed by integration into the host cell genome. HIV (human immunodeficiency virus) is the most extensively studied retrovirus and the cause of AIDS.
Retrovirus Structure and Classification
Retrovirus particles are approximately 100 nm in diameter, enveloped, and contain two identical copies of single-stranded positive-sense RNA. The viral core contains the capsid protein (CA), nucleocapsid protein (NC), reverse transcriptase (RT), integrase (IN), and protease (PR). The envelope glycoproteins SU (surface, gp120 in HIV) and TM (transmembrane, gp41 in HIV) mediate receptor binding and membrane fusion. Retroviruses are classified into simple retroviruses (such as murine leukemia virus) that encode only gag, pol, and env genes, and complex retroviruses (such as HIV and human T-lymphotropic virus) that encode additional regulatory and accessory genes including tat, rev, nef, vif, vpr, and vpu in HIV.
The Retroviral Replication Cycle
Entry begins with binding of the viral envelope glycoprotein to the host cell receptor, with HIV using CD4 as the primary receptor and either CCR5 or CXCR4 as a co-receptor. Fusion of the viral envelope with the cell membrane releases the viral core into the cytoplasm. Reverse transcription converts the viral RNA genome into double-stranded linear DNA within a reverse transcription complex, a process that is error-prone due to the lack of proofreading activity in reverse transcriptase, contributing to high genetic variability. The pre-integration complex, containing the viral DNA and integrase, is transported into the nucleus. Integration is catalyzed by integrase, which cleaves the host DNA and ligates the viral DNA into the host chromosome, creating a permanently integrated provirus that is replicated along with host cell DNA.
HIV Pathogenesis
Following transmission, HIV establishes infection in CD4+ T cells, macrophages, and dendritic cells. Acute infection is characterized by high viral load, rapid depletion of CD4+ T cells in mucosal tissues, and a flu-like syndrome. The immune system partially controls the infection, reducing viral load to a set point, but HIV establishes chronic infection with continuous viral replication and progressive CD4+ T cell decline. Without treatment, the CD4+ count eventually falls below 200 cells/µL, defining the onset of AIDS, characterized by susceptibility to opportunistic infections such as Pneumocystis jirovecii pneumonia, Mycobacterium avium complex, and Kaposi sarcoma (caused by human herpesvirus 8). HIV also causes direct damage to the immune system through chronic immune activation, exhaustion of T cell responses, and depletion of lymphoid tissue architecture.
Antiretroviral Therapy
Combination antiretroviral therapy (ART) targets multiple steps of the HIV replication cycle. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) such as tenofovir and emtricitabine are chain terminators that block reverse transcription. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz bind to a different site on RT, causing conformational inhibition. Protease inhibitors (PIs) such as darunavir block the cleavage of viral polyproteins, preventing maturation. Integrase strand transfer inhibitors (INSTIs) such as dolutegravir block integration. Entry inhibitors include the CCR5 antagonist maraviroc and the fusion inhibitor enfuvirtide. ART suppresses viral replication to undetectable levels, allows CD4+ T cell recovery, and prevents progression to AIDS and transmission to others, but does not eradicate HIV due to the persistence of latently infected cells.
HIV Latency and the Reservoir
HIV establishes latency in resting CD4+ T cells that harbor integrated provirus but do not produce viral particles. This latent reservoir is established within days of infection, is extremely stable with a half-life of approximately 44 months, and is not targeted by ART or the immune system. The reservoir is the main barrier to HIV cure. Latency reversal agents such as histone deacetylase inhibitors (vorinostat) and protein kinase C agonists are being tested in shock and kill strategies to reactivate latent virus and render cells susceptible to immune clearance.
Other Clinically Important Retroviruses
Human T-lymphotropic virus type 1 (HTLV-1) infects approximately 5–10 million people worldwide and causes adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. Unlike HIV, HTLV-1 causes proliferation rather than depletion of infected T cells and has a much lower mutation rate due to the absence of a strong error-prone replication cycle. Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome, representing ancient retroviral infections fixed in the germline, and have been domesticated for physiological functions including placental development through syncytin proteins.
HIV Prevention
Pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine reduces HIV acquisition risk by over 99% when taken consistently. Post-exposure prophylaxis (PEP) with a three-drug regimen started within 72 hours of exposure reduces infection risk. Treatment as prevention (TasP) means that people with undetectable viral load cannot transmit HIV to sexual partners (U=U, undetectable equals untransmittable). Vaccine development has been challenging due to HIV’s high genetic variability, extensive glycosylation of the envelope protein, and conformational masking of conserved epitopes, but broadly neutralizing antibodies targeting conserved regions of the HIV envelope have been identified and are being tested in passive immunization and vaccine strategies.
