The worldwide spread of HIV-1 indicates that the virus effectively counteracts innate, adapted, and intrinsic immunity. Despite its modest genome size (less than 10 kb) and its few genes, HIV-1 excels in taking advantage of cellular pathways while neutralizing and hiding from the different components of the immune system. Markedly, our understanding of pathogenesis is often derived from studies of subtype B viruses and non-human primate studies.
The HIV-1 life cycle is complex and its duration and outcome is dependent on target cell type and cell activation. In the early steps, HIV-1 gains access to cells without causing immediate lethal damages but the entry process can stimulate intracellular signal cascades, which in turn might facilitate viral replication.
The two molecules on the HIV-1 envelope, the external glycoprotein (gp120) and the transmembrane protein (gp41), form the spikes on the virion’s surface. During the entry process, gp120 attaches to the cell membrane by first binding to the CD4+ receptor. Subsequent interactions between virus and chemokine co-receptors (e.g., CCR5, CXCR4) trigger irreversible conformational changes. The actual fusion event takes place within minutes by pore formation, and releases the viral core into the cell cytoplasm. After the core disassembles, the viral genome is reverse transcribed into DNA by the virus’ own reverse transcriptase enzyme.
Related yet distinct viral variants can be generated during this process since reverse transcriptase is error prone and has no proofreading activity. At the midpoint of infection, the viral protein integrase in conjunction with host DNA repair enzymes inserts the viral genome into gene-rich, transcriptionally active domains of the host’s chromosomal DNA. An integrase binding host factor, LEDGF/p75 (lens epithelium-derived growth factor), facilitates integration, which marks the turning point by irreversibly transforming the cell into a potential virus producer. In the late steps, production of viral particles needs host driven as well as virus driven transcription. Viral proteins are transported to and assemble in proximity to the cell membrane. Virus egress from the cell is not lytic and takes advantage of the vesicular sorting pathway (ESCRT-I, II, III), which normally mediates the budding of endosomes into multivesicular bodies.
HIV-1 accesses this protein-sorting pathway by binding TSG101 via its late domain, a short sequence motif. Cleavage of the Gag-Pol poly-protein by the viral protease produces mature infectious virions.
Since cytoplasmic molecules of the producer cell and components from its cell surface lipid bilayer are incorporated into the new viral particle, virions bear characteristics of the cells in which they were produced. Incorporated host molecules can determine the virus’ phenotype in diverse ways (e.g., shape the replicative features in the next cycle of infection or mediate immune activation of bystander cells.
Studies of the early events that happen after HIV-1 breaches the mucosal barrier suggest the existence of a window period in which viral propagation is not yet established and host defences could potentially control viral expansion. The important co-receptors for HIV-1 infection are two chemokine receptors—CCR5 and CXCR4. Independently of the transmission route, most new infections are established by viral variants that rely on CCR5 usage.64 CXCR4-tropic viruses generally appear in late stages of infection and have been associated with increased pathogenicity and disease progression.
Compelling evidence from non-human primate models (e.g., simian immunodeficiency virus [SIV] infection of rhesus macaques) suggest that vaginal transmission results in infection of a small number of CD4+ T lymphocytes, macrophages, and dendritic cells located in the lamina propria. Potential pathways for virus transmission involve endocytosis, transcytosis, and virus attachment to mannose C-type lectin receptors (e.g., DC-SIGN) located on dendritic cells and macrophages.66 The initial replication takes place in the regional lymph organs (e.g., draining lymph nodes) and is composed of few viral variants, and leads to modest primary amplification. With migration of infected T lymphocytes or virions into the bloodstream, secondary amplification in the gastrointestinal tract, spleen, and bone marrow results in massive infection of susceptible cells.
In close temporal relation with the resulting peak of viraemia (e.g., 106 to 107 copies per mL plasma), clinical symptoms can be manifest during primary HIV-1 infection. The level of viraemia characteristic for the chronic phase of infection in an individual (viral set point) differs from the peak viraemia by one or two orders of magnitude. This reduction is largely attributed to HIV-1 specific CD8+ responses but target cell limitation could also play a part.
The viral population is most homogeneous early after transmission, but as viral quasi-species diversify in distinct biological compartments, mutant viruses that are resistant to antibody neutralisation, cytotoxic T cells, or antiretroviral drugs are generated and archived in long-lived cells (i.e., viral reservoirs).
A pronounced depletion of activated as well as memory CD4+ T cells located in the gut-associated lymphoid tissues has been seen in individuals identified early after infection.67 The preferential depletion of the CD4+ cells in the mucosal lymphoid tissues remains despite years of antiretroviral treatment, a striking observation that contrasts with the fact that the number of CD4+ T lymphocytes in the peripheral blood can return to normal under antiretroviral treatment.
A gradual destruction of the naive and memory CD4+ T-lymphocyte populations is the hallmark of HIV-1 infection, with AIDS being the last disease stage. Despite the frequent absence of symptoms during early and chronic phase, HIV-1 replication is dynamic throughout the disease. The half-life of a single virion is so short that half the entire plasma virus population is replaced in less than 30 minutes, and the total number of virions produced in a chronically infected person can reach more than 10¹P particles per day. The turnover rates of lymphocyte populations are upregulated many fold during HIV-1 infection, whereas cell proliferation decreases once viral replication is reduced by antiretroviral treatment. Different depletion mechanisms have been proposed, with an emerging consensus favouring generalised immune activation as cause for constant depletion of the CD4+ cell reservoir.
Immune activation predicts disease progression and, thus, seems to be a central feature of pathogenic HIV-1 infections. Recently, Nef proteins from SIV lineages that are non-pathogenic in their natural hosts (e.g., African green monkeys) have proved to down-regulate CD3-T-cell receptors, resulting in reduced cell activation and apoptosis.75 HIV-1 Nef fails to quench T-cell activation, possibly leading to the high degree of immune activation seen in infected people.
Understanding the mechanisms that lead to protection or long-lasting control of infection will guide vaccine development by providing correlates of protection. Natural resistance to HIV-1 infection is rare and varies greatly between individuals. Two groups—long-term non-progressors and highly exposed persistently seronegative individuals—have been studied widely to identify innate and acquired protective determinants (table 1).
Host resistance factors consist of human leucocyte antigen (HLA) haplotypes, autoantibodies, mutations in the promoter regions, and coding regions of the co-receptors CCR5 and CCR2, as well as the up-regulation of chemokine production Indeed, individuals encoding a truncated CCR5 version (CCR5Δ32) have slower disease progression (heterozygote) or are resistant to CCR5-using viruses (homozygote). The CCL3L1 gene encodes MIP1α, a CCR5 co-receptor ligand and chemokine with antiviral activity. Recent findings show that CCL3L1 gene copies vary individually and higher numbers of gene duplications result in reduced susceptibility to infection, possibly by competitive saturation of CCR5 co-receptor. Cytotoxic T-lymphocyte responses, helper T-cell functions, and humoral responses are some of the acquired factors that modulate the risk of transmission in highly exposed persistently seronegative individuals, and could also contribute to spontaneous control of replication in long-term non-progressors. The putative protective role of cytotoxic T-lymphocyte activity has been suggested in seronegative sex workers and in some long-term non-progressors.
Mammalian cells are not welcoming micro-environments, but rather deploy a defensive web to curb endogenous and exogenous viruses. HIV-1’s ability to circumvent these defences is as impressive as its efficiency to exploit the cellular machinery. APOBEC3G/3F and TRIM5α are recently described intrinsic restriction factors that are constitutively expressed in many cells. Both gene loci have been under strong selective pressure throughout primate evolution, indicating an ancient need to neutralise foreign DNA and maintain genome stability that precedes the current HIV-1 pandemic.
APOBEC3 enzymes (A3) belong to the superfamily of cytidine deaminases, a group of intracellular proteins with DNA/RNA editing activity. Most representatives of the APOBEC3 group have some mutagenic potential and restrict endogenous retroviruses and mobile genetic elements. The deaminases A3G, A3F, and A3B have potent antiviral activity, with the first two being expressed in cells that are susceptible to HIV-1 infection (T-lymphocytes, macrophages). HIV-1 evades APOBEC3 mutagenesis by expressing Vif, which leads to APOBEC3G/3F but not A3B degradation.
We still need to establish how the mechanisms of DNA editing and antiviral activity are interwoven, since some antiviral activity can be maintained despite defective DNA editing. The early replication block in non-stimulated CD4+ T cells has been attributed to low molecular mass complexes of APOBEC3G.
Hypermutated genomes in HIV-1 infected patients and mutations in Vif resulting in abrogated or differential APOBEC3 neutralisation capacity have been described. The degree to which APOBEC3G/3F mRNA expression predicts clinical progression remains an area of intensive investigation.
Several representatives of the heterogeneous family of tripartite motif proteins (TRIM) inhibit retroviruses in a species-specific manner. TRIM5α from rhesus macaques and African green monkeys inhibit HIV-1 replication, whereas the human homologue is inactive against SIV and HIV-1, leading to the recorded susceptibility of human cells to both viruses.
Rhesus TRIM5α recognises the capsid domain of HIV-1 Gag and manipulates the kinetics of HIV-1 core disassembly within minutes after cell entry. Thus, experimental approaches to render HIV-1 resistant to rhesus TRIM5α could lead to immunodeficiency viruses capable of replicating in rhesus macaques. Such a non-primate model would allow testing of antiviral treatment and vaccine interventions with HIV-1 viruses instead of SIV or SIV/HIV chimeric viruses.
One is at greatest risk of HIV/AIDS if one:
• Has unprotected sex. Unprotected sex means having sex without using a new latex or polyurethane condom every time. Anal sex is more risky than is vaginal sex. The risk increases I people who have multiple sexual partners.
• Have another STI. Many sexually transmitted infections (STIs) produce open sores on the genitals. These sores act as doorways for HIV to enter the body.
• Use intravenous drugs. People who use intravenous drugs often share needles and syringes. This exposes them to droplets of other people’s blood.
• Are an uncircumcised man. Studies indicate that lack of circumcision increases the risk for heterosexual transmission of HIV.