Sorting out the complexities of HIV-1 fitness

The impact of HIV-1 fitness on disease progression and antiretroviral resistance has gained considerable attention in the HIV-1 research community. However, relevance is still marred by a rather vague definition of fitness, i.e. an organism's replicative capacity/adaptability in a given environment. Difficulties in delineating an environment lead to the obvious question 'Is replicative capacity of an HIV-1 isolate the same as fitness in the infected individual?' The simple answer is 'no'. However, a more systematic response suggests that fitness in each layered environment may be interrelated but not necessarily consequential. For example, the ability of wild-type HIV-1 reverse transcriptase (RT) to out-compete the drug-resistant RT for substrate in the absence of drug may be consequential to the ability of wild-type virus to compete with the drug-resistant strain in susceptible cells, within a single human host, or even in the human population [¹]. Unless selective drug pressure is applied, the drug-resistant virus remains less fit than wild-type in all environments [²]. However, selection of the most virulent isolate of a lethal parasite cannot be maintained becaue of the ultimate extinction of both host and pathogen. Recent studies have suggested that the increased replicative capacity of an infecting HIV-1 isolate is associated with more rapid disease progression [³]. Because the probability of HIV-1 transmission may be related to survival time, the more 'fit' virus infecting rapid progressors may actually be spread less efficiently in the human population. A recent study by Kaleebu et al. [⁴] showed faster rates of disease progression in Ugandan individuals infected with subtype D compared with subtype A HIV-1 isolates, even though subtype D is decreasing in prevalence.

We have written a lengthy article to review the plethora of HIV-1 fitness/replication studies and their implications on both disease progression and the epidemic [¹]. Unfortunately, there are several discrepancies in this HIV-1 fitness research that arise from: (i) the use of different viral replication assays (e.g. mono, single-cycle or competitive infections); (ii) the use of different host cells (e.g. cell lines versus primary human cells); and (iii) the use of primary HIV-1 isolates propagated from patient samples versus virus clones containing specific genomic regions or mutations [²]. Although there are advantages with each of these assays, the term 'relative fitness' in the HIV-1 field has been applied loosely and is not defined by a specific environment, assay, or virus properties [¹]. This ambiguity leads to difficulties in data interpretation and directing future research studies.