Modeling sequence evolution in acute HIV-1 infection

Abstract

We describe a mathematical model and Monte-Carlo (MC) simulation of viral evolution during acute infection. We consider both synchronous and asynchronous processes of viral infection of new target cells. The model enables an assessment of the expected sequence diversity in new HIV-1 infections originating from a single transmitted viral strain, estimation of the most recent common ancestor (MRCA) of the transmitted viral lineage, and estimation of the time to coalesce back to the MRCA. We also calculate the probability of the MRCA being the transmitted virus or an evolved variant. Excluding insertions and deletions, we assume HIV-1 evolves by base substitution without selection pressure during the earliest phase of HIV-1 infection prior to the immune response. Unlike phylogenetic methods that follow a lineage backwards to coalescence, we compare the observed data to a model of the diversification of a viral population forward in time. To illustrate the application of these methods, we provide detailed comparisons of the model and simulations results to 306 envelope sequences obtained from 8 newly infected subjects at a single time point. The data from 6/8 patients were in good agreement with model predictions, and hence compatible with a single-strain infection evolving under no selection pressure. The diversity of the samples from the other two patients was too great to be explained by the model, suggesting multiple HIV-1-strains were transmitted. The model can also be applied to longitudinal patient data to estimate within-host viral evolutionary parameters.

Cross-Neutralization Activity of Single-Chain Variable Fragment (scFv) Derived from Anti-V3 Monoclonal Antibodies Mediated by Post-Attachment Binding

“…However, most of the anti-V3 Abs only neutralize tier 1 viruses, and they poorly neutralize primary isolates with a tier 2 phenotype (17). The V3 epitope is hidden within the Env trimer in most primary HIV-1 isolates, because of masking by V1/V2 loops and carbohydrates in non-triggered Env (18,19) The interaction between gp120 and CD4, which initiates HIV-1 entry, induces conformational changes in the Env trimer, followed by exposure of the V3 loop between the gp120 and the target cell membrane (6,7). However, it is difficult for anti-V3 antibodies to bind to their epitope following CD4-gp120 interaction because IgG, with an average size of 115 Å, is too large to achieve the close physical proximity to gp120 and cellular membrane, which is required for access to the V3 loop (20).…”

Biology as Population Dynamics: Heuristics for Transmission Risk

“…One interesting finding from studies of early infection is that the pattern of genetic diversity of HIV virus in the weeks after transmission is only consistent, in about three quarters of infections, with the transmission of a single genotype, which has typically been interpreted as the transmission of a single virion. 10 An alternative view is that descendants of other variants may be undetectable because critical early events, or relatively minor differences in replicative fitness, accumulate exponentially over viral life cycles to produce a strong dominance by the descendants of one of several founder variants. Nevertheless, it is biologically plausible to model transmission risk as the likelihood of establishing a single founder strain, which facilitates simplifications of the models relative to a more general case where there are many possible pathways to infection, involving a wide range of possible numbers of transmitted virions.…”

Nucleic Acid Testing for HIV-1 Diagnosis and Monitoring

“…The time elapsed between HIV exposure and the burst of viremia is denominated eclipse period. [17] When viral replication starts, HIV-1 viral load tends to be exceedingly high, usually with the detection of more than 1 million of HIV RNA copies/mL. [17] Once host immune specific humoral and cellular immunity starts to emerge, viral load tends to decrease to basal values which tend to be constant for the rest for life, and usually affected only by antiretroviral treatment.…”

“…The first HIV marker that can be detected is the RNA of virions, which occurs after 17 days (13 to 28), followed by the proviral DNA at the 20 th day (18 to 34), followed by the detection of the p24 antigen, which occurs at day 22 (18 to 34). [17] All those markers can be readily used to shorten up the period to detect HIV-1 infection after the exposure event.…”

“…Plasma HIV-1 RNA is detected by commercial viral load assays, whereas HIV DNA in PBMCs is detected by home brew PCE assays. [17] www.intechopen.com after vertical exposure. Either of the above mentioned tests, the virion RNA, proviral DNA and p24 antigen can be of utility in the detection of HIV infection after the eclipse period and before fully HIV-1 seroconversion.…”