Contribution of HIV-1 genomes that do not integrate to the basic reproductive ratio of the virus

Recent experimental data indicate that HIV-1 DNA that fails to integrate (from now on called uDNA) can by itself successfully produce infectious offspring virions in resting T cells that become activated after infection. This scenario is likely important at the initial stages of the infection. We use mathematical models to calculate the relative contribution of unintegrated and integrated viral DNA to the basic reproductive ratio of the virus, R0, and the models are parameterized with preliminary data. This is done in the context of both free virus spread and transmission of the virus through virological synapses. For free virus transmission, we find that under preliminary parameter estimates, uDNA might contribute about 20% to the total R0. This requires that a single copy of uDNA can successfully replicate. If the presence of more than one uDNA copy is required for replication, uDNA does not contribute to R0. For synaptic transmission, uDNA can contribute to R0 regardless of the number of uDNA copies required for replication. The larger the number of viruses that are successfully transmitted per synapse, however, the lower the contribution of uDNA to R0 because this increases the chances that at least one virus integrates. Using available parameter values, uDNA can maximally contribute 20% to R0 in this case. We argue that the contribution of uDNA to virus reproduction might also be important for continued low level replication of HIV-1 in the presence of integrase inhibitor therapy. Assuming a 20% contribution of uDNA to the overall R0, our calculations suggest that R0=1.6 in the absence of virus integration. While these are rough estimates based on preliminary data that are currently available, this analysis provides a framework for future experimental work which should directly measure key parameters.