HIV/AIDS epidemiology, pathogenesis, prevention, and treatment

Abstract

The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Research has deepened our understanding of how the virus replicates, manipulates, and hides in an infected person. Although our understanding of pathogenesis and transmission dynamics has become more nuanced and prevention options have expanded, a cure or protective vaccine remains elusive. Antiretroviral treatment has transformed AIDS from an inevitably fatal condition to a chronic, manageable disease in some settings. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most affected by increasing morbidity and mortality. This Seminar provides an update on epidemiology, pathogenesis, treatment, and prevention interventions pertinent to HIV-1.

Figure 1. Worldwide distribution of HIV-1 infections, modes of transmission, and HIV-1 subtypes

HSex=heterosexual. MSM=Men who have sex with men. IDU=injection drug users. Based on Joint UNAIDS and WHO AIDS epidemic update December, 2005.

Figure 2. Phylogenetic relation of lentiviruses in man and non-human primates

The HIV-1 pandemic is largely due to viral isolates belonging to the HIV-1 M-group, with HIV-1 subtype C being the most prevalent (red). Recombinant circulating forms cluster with the M-group but have been omitted for clarity. HIV-1 M group and the contemporary SIV strains identified in wild chimpanzees in Cameroon (SIVcpzLB7/EK528) are highlighted. HIV-1 sequences cluster closely with SIV from chimpanzees (SIVcpz), whereas HIV-2 resembles SIV from macaques and sooty mangabeys (SIVmac/SIVsm).

Figure 3. HIV-1 is a retrovirus that encodes three structural genes (Gag, Pol, and Env)

(A) Envelope glycoproteins gp120/41 form the spikes on the virion’s surface. During maturation the gag protein is cleaved and Gag p24 forms the core. The viral genome, viral reverse transcriptase (RT), integrase as well as a number of host proteins are encapsidated. (B) Dir erent steps of the viral life cycle on a cellular level and the potential targets for treatment interventions. (C) HIV-1 has evolved strategies to counteract the restriction factors TRIM5α and APOBEC3G/3F. If left unchecked by HIV-1 Vif, APOBEC3G/3F is encapsidated into the egressing virion, and on infection of a target cell leads to G-to-A hypermutations in the viral genome. Rhesus TRIM5α inhibits HIV-1 replication early after infection of the target cell before the step of reverse transcription.

Figure 4. The course of HIV-1 infection defined by the level of viral replication

Plasma viraemia (top), and dynamic changes of the CD4+ T-lymphocyte compartments (bottom). Primary infection characterised by high plasma viraemia (red line, top), low CD4 cells (green line, bottom), and absence of HIV-1 specific antibodies (orange line, bottom). Viraemia drops as cytotoxic CD8+ T-lymphocytes (CTL) develop (blue line, bottom) and an individual viral-load set point is reached during chronic infection. Viral set points dir er greatly among individuals (eg, red dotted line, top) and predict disease progression. Viral diversity increases through out the disease (closed circles, top). The risk of transmission is highest in the first weeks when viraemia peaks (closed circles, top). GALT=gut-associated lymphoid tissues.

Figure 5. Timeline of microbicide development of different product generation with trial initiation dates as reference

N9=nonoxonol-9. CS=cellulose sulphate.

Figure 6. Selected observations, scientific developments, and treatment options pertinent to HIV-1/AIDS

Estimates place the cross species transmission events leading to the worldwide spread of HIV-1 to the early decades of the 20th century. Numbers circled by a hexagon identify the specific year of an event. PEPFAR=President’s Emergency Plan for AIDS Relief.