Figure 1. Electron micrograph of HIV-1. Virus particles (virions) are surrounded by a lipid envelope in which are embedded the trimeric Env protein complexes that mediate attachment and entry. Lining the inside of the envelope is the viral matrix protein, which plays a key role in assembly of the virus particle. Inside the envelope is a conical cylinder called the core, which is formed by the viral capsid protein. Inside the capsid are two copies of the viral genomic RNA bound by the nucleocapsid protein. The matrix, capsid and nucleocapsid proteins are all encoded by the gag gene. The particle also contains the RT and integrase enzymes that are needed after entry of the virus into host cells.

Figure 2. Natural history of HIV-1 infection. (a) Natural history in the absence of effective treatment. During primary HIV-1 infection, virus present in the infecting inoculum replicates, eventually producing a high level of viraemia (red line). CD4 counts (blue line) may fall during this period, but increase again as the immune response to HIV-1 develops and the level of viraemia falls. Following primary infection, the level of plasma virus does not fall to zero, but rather to a steady state level (the ‘set point’) that differs among patients and that determines the rate of loss of CD4 cells during the prolonged asymptomatic period between primary HIV-1 infection and the development of AIDS. When the CD4 count falls below 200 cells L^–1, patients become susceptible to life-threatening opportunistic infections. (b) The effect of treatment with highly active antiretroviral therapy (HAART). When patients are started on an effective regimen of multiple antiretroviral drugs, plasma virus levels drop rapidly in the first 2 weeks of treatment, reflecting the short plasma half-life of the virus and the short half-life of most productively infected cells. The decline in plasma virus shows a second, slower phase that is due to turnover of a second population of cells with a longer half-life. However, within 1–4 months, plasma virus levels fall below the limit of detection of current RT-PCR assays. CD4 counts increase and opportunistic infections cease. Nevertheless, the virus persists through various mechanisms, including latency (see Figure 3), and a rebound in plasma viraemia occurs if therapy is stopped.

Figure 3. Model of the establishment of a latent reservoir for HIV-1. The normal T-cell physiology of T-cell activation is shown on the left. Upon initial encounter with the foreign microbial antigens (Ag) that they are programmed to recognize, naive CD4+ T cells enlarge, proliferate and carry out their helper functions. Some of these activated cells survive and go back to a resting state as memory cells, the biological function of which is to survive for long periods of time, allowing future responses to the same Ag. HIV-1 readily infects activated CD4+ T cells, progressing quickly through the steps of entry, reverse transcription, integration of the viral genome (red line) into host cell DNA, virus gene expression and virus production. Most of the productively infected cells die quickly as a result of either viral cytopathic effects or of killing by cytotoxic T lymphocytes. Infrequently, activated T cells that have integrated HIV-1 DNA survive long enough to revert back to a resting state. This results in the presence of integrated HIV-1 DNA in a cell whose biological function is to survive for years. In these resting cells, HIV-1 gene expression is largely turned off, due to the fact that the HIV-1 regulates expression of its own genes using host transcription factors that are turned on in activated cells and turned off in resting cells. In this state of postintegration latency, the virus is not detected by the immune system. Antiretroviral drugs, which block reverse transcription or virus particle maturation, have no effect on the preexisting pool of latently infected cells. For these reasons, latently infected cells represent a major barrier to HIV-1 eradication.