Virus-Host Gene Interactions Define HIV-1 Disease Progression

Abstract

In this chapter, we will review recent research on the virology of HIV-1 transmission and the impact of the transmitted virus genotype on subsequent disease progression. In most instances of HIV-1 sexual transmission, a single genetic variant, or a very limited number of variants from the diverse viral quasi-species present in the transmitting partner establishes systemic infection. Transmission involves both stochastic and selective processes, such that in general a minority variant in the donor is transmitted. While there is clear evidence for selection, the biological properties that mediate transmission remain incompletely defined. Nevertheless, the genotype of the transmitted founder virus, which reflects prior exposure to and escape from host immune responses, clearly influences disease progression. Some escape mutations impact replicative capacity, while others effectively cloak the virus from the newly infected host's immune response by preventing recognition. It is the balance between the impact of escape mutations on viral fitness and susceptibility to the host immunogenetics that defines HIV-1 disease progression.

Keywords: HIV pathogenesis; HIV transmission; Immune escape; Replicative capacity; Transmitted founder virus.

Figure 1.. Potential barriers to HIV transmission across the genital mucosa.

During transmission, the virus encounters a number of barriers to infection including mucous and epithelial layers that can block access to target cells. However, viruses can penetrate host defenses through temporary breaks in the epithelium or dendritic cell sampling the mucosal environment. The entering viruses must interact with susceptible CD4⁺ CCR5⁺ T cells to propagate since entry into non-permissive resting CD4⁺ T cells will result in non-productive infection. Similarly, if the RC of the virus is unable to sustain a spreading infection (R₀<1.0), even infection of susceptible cells will not result in dissemination. It is likely that viruses with a replicative advantage will outcompete those that replicate less efficiently. Initial target cells are most likely susceptible CD4⁺ CCR5⁺ T cells, a majority of which may be of a Th17 lineage, but infection of macrophages and dendritic cells has also been reported. These cells can replicate virus locally or traffic to local secondary lymphoid structures, though virus could also diffuse there directly. Once virus reaches local lymph nodes and disseminates throughout the body, specifically to the gut mucosa, viral load increases exponentially in the blood. Approximately 70–80% of mucosal infections are established by single variants. Adapted from Ende and Hunter (Ende et al. 2017)

Figure. 2.. Selection bias in heterosexual HIV-1 transmission.

The odds that the transmitting partner’s amino acid will be transmitted to the recipient is a function of the relative frequency of the amino acid in the donor virus quasi-species. The plot shows the empirical transmission probability (odds on a log10 scale) of a variant as a function of the relative in vivo frequency of the variant in the donor quasi-species, with a near 1-to-1 mapping for variants that match cohort consensus. In contrast, polymorphisms are uniformly less likely to be transmitted. Adapted from (Carlson et al. 2014)

Figure 3.. The balance between transmitted viral characteristics and early CTL immune responses determines disease progression.

High pre-adaptation and RC of the transmitted virus will tip the scale in favor of rapid disease progression. Pre-adaptation leads to impaired cytotoxic immune responses since the transmitted escape mutations prevent HLA molecules from presenting HIV epitopes (1) or lead to the presentation of epitopes that are poorly recognized by the TCR on the CTLs (2). High replication contributes with larger viral loads and proportions of infected cells, including the subsets associated with latency. On the other hand, large numbers of non-associated polymorphisms and strong, poly-functional cytotoxic immune responses tip the scale in favor of slow disease progression or control. These polymorphisms impair virus replication (3) but may as well negatively impact innate immune responses while the activity of strong, poly-functional CTLs contributes to reducing viral load (4).