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Review
. 2015 Jul;13(7):414-25.
doi: 10.1038/nrmicro3471. Epub 2015 Jun 8.

Bottlenecks in HIV-1 transmission: insights from the study of founder viruses

Sarah B Joseph  1 , Ronald Swanstrom  2 , Angela D M Kashuba  3 , Myron S Cohen  4
Affiliations
Review

Bottlenecks in HIV-1 transmission: insights from the study of founder viruses

Sarah B Joseph et al. Nat Rev Microbiol. 2015 Jul.

Abstract

HIV-1 infection typically results from the transmission of a single viral variant, the transmitted/founder (T/F) virus. Studies of these HIV-1 variants provide critical information about the transmission bottlenecks and the selective pressures acting on the virus in the transmission fluid and in the recipient tissues. These studies reveal that T/F virus phenotypes are shaped by stochastic and selective forces that restrict transmission and may be targets for prevention strategies. In this Review, we highlight how studies of T/F viruses contribute to a better understanding of the biology of HIV-1 transmission and discuss how these findings affect HIV-1 prevention strategies.

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Figures

Figure 1
Figure 1. The transmitted/founder virus is shaped by multiple genetic bottlenecks
Chronically infected individuals have extremely diverse HIV-1 populations in their blood. Some viruses from the blood seed the genital tract of the donor, where the resulting viral population is less diverse than in the blood and is often dominated by a few clonally amplified variants. It is unknown whether replication in the genital tract selects for specific phenotypes. Viruses sampled from the donor genital tract are present in the transmission fluids (cervicovaginal mucus, semen or rectal secretions). These fluids may contain proteins that enhance (for example, semen-derived enhancers of virus infection) or reduce (for example, cytokines, chemokines, antimicrobials, lectins and autologous antibodies) viral infectivity. Differential sensitivity to these proteins could select for specific viral phenotypes. The vast majority of viruses within the transmission fluid do not penetrate the genital or rectal mucosa of the recipient. Damage due to sexually transmitted infections or intercourse can increase the ability of viruses to penetrate the mucosa. Most of the viruses that are able to infect the recipient genital tract have a low reproductive rate (R0<1) owing to low densities of target cells, low viral fitness or susceptibility to host defences (such as phagocytosis or production of interferons) and will not contribute to the systemic infection. Typically, when a systemic infection is established after sexual exposure to HIV-1, the initial viral population in the recipient's blood will be genetically homogeneous because it was established from a single viral genotype (the transmitted/founder virus) that was able to replicate in the recipient genital tract. On progression to the chronic stages of infection, infected individuals display extremely diverse HIV-1 populations in their blood.
Figure 2
Figure 2. Compartmentalization of genital tract-specific viral lineages
HIV-1 populations in the blood are genetically diverse during chronic infection, but genital tract (GT)-specific lineages can be either homogeneous or diverse. a. Clonally amplified viruses are produced when one or a few cells (most likely T cells) are infected with very similar viruses. Phylogenetic analyses illustrate that clonally amplified viruses that are present in the GT (blue) are much less diverse than viruses that are present in the blood (red, orange and pink). b. Viral replication in the GT for many generations can produce diverse, GT-specific lineages (blue and green) that are phylogenetically distinct from viruses that are present in the blood (red, orange and pink). These diverse lineages may have adapted to replication in different cell types (such as macrophages) and/or evolved independently in different parts of the GT.
Figure 3
Figure 3. Selection of transmitted/founder virus phenotypes
Transmitted/founder (T/F) HIV-1 viruses may be enriched for phenotypes that increase the probability of transmission. a. Viruses may have a low probability of being transmitted if they are sensitive to autologous antibodies present in the transmission fluids, such as semen or cervicovaginal mucus. b. Highly glycosylated viruses may also have a lower probability of being transmitted if they are bound by lectins in the transmission fluid. c. Glycans on the surface of viruses may restrict their migration through the transmission fluid. d–f. In the genital submucosa of the recipient, viruses may have a reduced probability of transmission if their Env protein is poorly adapted to entering cells in that tissue (part d). Similarly, a virus may have a reduced probability of transmission if it replicates slowly because it has a low-fitness genotype or it preferentially infects target cells that do not replicate viruses rapidly (for example, macrophages and resting CD4+ T cells). In this case, the basic reproductive rate of the virus (R0, which is an estimate of the number of cells that will be infected from a single infected cell) will be lower than 1 and the virus will be lost (part e). By contrast, the probability of transmission may be increased if a virus replicates rapidly because it has a high-fitness genotype or an ability to preferentially infect target cells that rapidly amplify virus (for example, activated CD4+ T cells). In this case, the R0 of the virus will be higher than 1 and the virus can establish an infection and will eventually be present in the blood of the recipient (part f).
Figure 4
Figure 4. Characteristics of transmitted/founder viruses
The dfferent cell types that are available for infection by HIV-1 transmitted/founder (T/F) viruses in the genital tract of the recipient differ greatly in their surface expression of the CD4 receptor and of the C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) co-receptors. For example, CD4+ T cells express much higher densities of CD4 than do macrophages. Importantly, memory CD4+ T cells express both the CCR5 and the CXCR4 co-receptors, but for simplicity reasons, only one of the co-receptors is displayed in each cell. a. Most viral lineages have adapted to replicating in CD4+ T cells. These T cell-tropic viruses are inefficient at entering cells expressing low levels of CD4 (such as macrophages) and require high levels of CD4+ for entry (such as those expressed by CD4+ T cells). T cell-tropic viruses can be further divided by whether they use the CCR5 or the CXCR4 co-receptor. Most T/F viruses use the CCR5 co-receptor,, making them R5 T cell-tropic. These viruses are frequently transmitted to new individuals. b. A few HIV-1 lineages have been identified, mostly in the central nervous system of people at end-stage disease, that primarily replicate in macrophages. These macrophage‑tropic viruses are able to enter cells expressing low levels of CD4. However, no macrophage-tropic T/F viruses have been reported, suggesting that these viruses are not transmitted to new individuals. c. Some T cell-tropic viruses can use the CXCR4 co-receptor, making them X4 T cell-tropic. These viruses are transmitted occasionally.
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