HIV-1 pathogenesis: the virus

Abstract

Transmission of HIV-1 results in the establishment of a new infection, typically starting from a single virus particle. That virion replicates to generate viremia and persistent infection in all of the lymphoid tissue in the body. HIV-1 preferentially infects T cells with high levels of CD4 and those subsets of T cells that express CCR5, particularly memory T cells. Most of the replicating virus is in the lymphoid tissue, yet most of samples studied are from blood. For the most part the tissue and blood viruses represent a well-mixed population. With the onset of immunodeficiency, the virus evolves to infect new cell types. The tropism switch involves switching from using CCR5 to CXCR4 and corresponds to an expansion of infected cells to include naïve CD4(+) T cells. Similarly, the virus evolves the ability to enter cells with low levels of CD4 on the surface and this potentiates the ability to infect macrophages, although the scope of sites where infection of macrophages occurs and the link to pathogenesis is only partly known and is clear only for infection of the central nervous system. A model linking viral evolution to these two pathways has been proposed. Finally, other disease states related to immunodeficiency may be the result of viral infection of additional tissues, although the evidence for a direct role for the virus is less strong. Advancing immunodeficiency creates an environment in which viral evolution results in viral variants that can target new cell types to generate yet another class of opportunistic infections (i.e., HIV-1 with altered tropism).

Figure 1.

Time course of a typical HIV-1 infection with the appearance of host range variants late. The time course for different components of the infection are shown. There is an initial loss of CD4⁺ T cells during acute infection followed by a partial recovery and then a slow decay during the period of clinical latency (black line). There is an initial viremia of the transmitted virus that uses CCR5 (R5) and requires high levels of CD4 to enter cells, and this virus establishes a set point during the period of clinical latency (CD4^Hi R5 T-cell-tropic, green line). With the loss of CD4⁺ T cells there is increasing immunodeficiency (AIDS, including NeuroAIDS), a trend toward increasing viral load, and in a subset of subjects the appearance of host range variants that evolve to use a different coreceptor (X4 T-cell-tropic, red line) or evolve the ability to infect cells, presumably macrophages, with low levels of CD4 (CD4^Low R5 M-phage-tropic, blue line).

Figure 2.

Evolution of host range variants. In this model the variant of HIV-1 that is replicating in memory T cells (requiring high levels of CD4 on the surface of the cell and using CCR5 as the coreceptor, shown in green) is exposed to reduced host surveillance in the form of reduced selective pressure from antibodies. This allows the virus to evolve such that the Env protein assumes a more open conformation that allows increased binding to CD4. The open conformation may also expose a latent low level tropism for CXCR4. These changes potentiate the subsequent evolution to use CXCR4 efficiently (X4 virus—red) or to use CD4 more efficiently (macrophage tropism—blue).

Figure 3.

Phylogenetic trees demonstrating different relationships between viral populations. In these trees are examples of viral populations in blood (red) and semen (blue). On the left is an example of well-mixed populations with the sequences derived from blood and semen intermingled. In the middle is an example of clonal amplification (blue bars) in which a nearly homogeneous set of sequences appears only in the semen creating a population that is distinct from the blood. On the right is an example of compartmentalization in which the sequences in the semen are distinct from the bulk of the sequences in the blood. These two lineages are indicated by the circles. In addition, sequences present in the seminal tract appear to have migrated back into the blood compartment. (These trees were originally published in Anderson et al. 2010; reprinted with permission from the author.)