Retroviruses: General Biology and HIV Structure

RNA genome. Retroviruses carry a positive-sense, single-stranded RNA genome, but do not replicate as RNA viruses in the conventional sense. The genome is first copied into DNA. This replication strategy sets the family apart from every other virus group.

Reverse transcriptase is the defining retroviral enzyme. It is packaged within the virion because it is required immediately on entry and has no host cell equivalent. It catalyses synthesis of a DNA copy of the viral RNA genome.

The enzyme lacks proofreading capability. This directly contributes to the very high retroviral mutation rate. For HIV, it also underlies extensive quasispecies diversity and the corresponding difficulty of durable immune control or vaccine design.

Integrase is a second virion-packaged enzyme. It inserts the newly synthesised viral DNA copy into the host cell chromosome. This step is unique among viruses: no other virus family achieves stable integration of its genetic material into host chromosomal DNA as an obligatory part of its normal replication cycle.

Protease is a third key retroviral enzyme. During maturation it cleaves large polyprotein precursors into their final, functional structural and enzymatic proteins. This step is essential for producing infectious progeny virions and is the specific target of the protease inhibitor antiretroviral drug class.

Provirus formation is the term for the integrated viral DNA copy once inserted into the host chromosome. It is a permanent, heritable part of that host cell's genome, replicated alongside the host's own DNA every time the host cell divides.

Host genome integration is the direct consequence of provirus formation. Because the viral genetic material becomes physically part of the host chromosome, no mechanism that leaves the host cell alive can eliminate it. This underlies the essential incurability of established retroviral infection with currently available therapy.

Suppression of active replication is achievable, but elimination of the integrated proviral reservoir is not.

HIV-1 versus HIV-2. These are two genetically distinct but related viruses. Both cause progressive immunodeficiency through the same CD4 T cell tropism and mechanism, but they differ in global distribution and clinical behaviour. HIV-1 causes the overwhelming majority of infections worldwide and is the focus of virtually all HIV-related clinical and research content.

HIV-2 is concentrated predominantly in West Africa. Compared with HIV-1, it has generally lower transmissibility, a longer typical asymptomatic period, and slower progression to clinical immunodeficiency. The underlying pathogenic mechanism, CD4 depletion, is the same.

Viral structure. HIV is an enveloped retrovirus, icosahedral though sometimes described as conical given the internal capsid geometry. It contains two copies of the positive-sense RNA genome. This diploid arrangement is relevant to the virus's capacity for recombination when a cell is co-infected by two genetically distinct HIV variants.

The virion also packages the three key enzymes: reverse transcriptase, integrase and protease.

gp120 is the outer envelope glycoprotein. It mediates the initial, specific binding to the host cell's CD4 receptor. Binding induces a conformational change, after which it binds a chemokine coreceptor, CCR5 or CXCR4.

It is the principal target of neutralising antibody. HIV's extensive antigenic variability, a direct consequence of the high reverse transcriptase mutation rate, makes durable, broadly neutralising antibody responses difficult to generate and sustain. This is a central, long-standing obstacle to HIV vaccine development.

gp41 is the transmembrane envelope glycoprotein. It anchors gp120 to the viral envelope. After the gp120-receptor and coreceptor binding sequence, it mediates membrane fusion, which delivers the viral capsid into the host cell cytoplasm. It is the specific molecular target of the fusion inhibitor antiretroviral drug class.

CD4 receptor is the primary, essential receptor for HIV entry. It is expressed predominantly on CD4 T helper lymphocytes, whose progressive depletion defines the clinical course of untreated HIV infection.

It is also expressed at lower density on macrophages and dendritic cells. These are target cells and a persistent cellular reservoir that contributes to the latent infection pool, which current antiretroviral therapy cannot eliminate.

CCR5 is the principal chemokine coreceptor used by macrophage-tropic (M-tropic or R5-tropic) HIV strains. This is the dominant viral tropism during early and chronic infection in the great majority of patients.

Individuals homozygous for a specific CCR5 mutation, CCR5-delta32, are highly resistant to HIV-1 infection via sexual and mucosal transmission. This natural genetic resistance has directly informed experimental curative approaches. Stem cell transplantation from CCR5-delta32-homozygous donors has produced a small number of documented functional HIV cures in patients requiring transplantation for an unrelated haematological malignancy.

CXCR4 is the alternative chemokine coreceptor used by T-cell-tropic (T-tropic or X4-tropic) HIV strains. These tend to emerge later in untreated infection in a proportion of patients. Their emergence is associated with more rapid CD4 decline and disease progression. This pattern of tropism evolution is recognised but not universal.