By Roberto Fernandez-Larsson, Ph.D.*
New light on how HIV is transmitted
People that have been HIV-infected for some time usually harbor swarms of slightly different, variant viruses at the same time, usually termed “quasispecies.” Much less is known about the variant or variants that are transmitted from one adult to another or from mother to child.
A group led by Eric Hunter and colleagues at the University of Alabama, Birmingham (UAB) has now studied a group of eight heterosexual discordant couples in Zambia to determine the evolutionary relationship of donor and recipient viruses (Science 303: 2019; 2004), asking the question, what are the characteristics of the virus variants that infect the new host? This information is important to researchers because the characteristics of these variants could be exploited in vaccine design.
They found that the glycoprotein gp120 of transmitted virus variants in donor-recipient pairs were more likely to contain shorter variable regions (V1 and V4) than the majority of the viruses in the donor quasispecies. The shorter variable regions also resulted in the absence of N-linked glycosylation sites, where the sugar parts of the molecule attach to gp120. Hunter and colleagues believe that this loss of amino acids and sugars expose the region of the HIV gp120 that binds to the cellular receptor CD4, making it easier for these variants to infect host cells and increasing their infectivity. Therefore, they claim, it is most likely that the viruses that ultimately establish infection through heterosexual contact are more fit for this purpose than other viruses in the quasispecies.
Neutralization studies were conducted with virions pseudotyped with donor and recipient Envs. Recipient pseudotypes, made with Envs from viruses from newly infected patients, were as much as ten times more sensitive to neutralization by plasma from the linked donors than the donor pseudotypes. Virus variants in patients with long-established infections are usually not sensitive to neutralization by plasma isolated from those patients at the same time.
But the researchers themselves caution that because of the limitations of the sampling used, they “cannot distinguish between a true transmission bottleneck, transmission of the predominantly replicating form in genital tissues, or transmission of multiple forms followed by outgrowth of a particular variant.” The latter possibility is particularly troublesome for vaccine design because it would entail more than one variant being transmitted to the new host.
Jon Cohen, in a commentary appearing in the same issue of Science, quotes virologist Douglas Richman (University of California, San Diego) as saying he has evidence contrary to the UAB data in his own matched donor-recipient pairs study, a group of predominantly homosexual men.
CTL escape variants are not forever
It has been extensively demonstrated that during HIV infection, the cellular immune response exerts selective pressure on the virus and drives a within-patient adaptive evolution. As a result, new virus variants appear that escape recognition by the original CD8+ cytotoxic T lymphocytes (CTL) response. These escape variants have been associated with a loss of immune recognition and progression to AIDS.
What happens if these escape variants are transmitted to a new host? If these escape mutations, and even new ones derived from them, could propagate in populations this could undermine the efficacy of CTL-based vaccines designed on specific CTL epitopes or even consensus epitopes. Two new papers in Nature Medicine shed light on this problem and suggest that this may not be the case.
In a study with SIV-infected macaques (Nat. Med. 10: 275; 2004), David Watkins (University of Wisconsin, Madison) and colleagues observed that escape variants in a heterogeneous SIV isolate were lost upon passage to new animals. They used cloned SIV bearing escape mutations in three immunodominant CTL epitopes (3x SIV) to infect macaques, and followed viral evolution after infection. They found that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. They characterized thein vitro growth properties of clonal viruses encoding escape mutations in all three epitopes and found that 3x SIV replication lagged behind that of wild-type SIV in the first 96 hours in culture. They construed that escape from CTL responses may exact a cost to viral fitness, the ability of the virus to replicate at normal levels.
In the companion paper in the same issue of the journal (Nat. Med. 10: 282; 2004), Philip Goulder (University of Oxford) and colleagues studied the same problem in humans infected with HIV from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control. They found two contrasting outcomes. In the first case — which they hypothesize is associated with a fitness cost to the virus — they observed reversion of a CTL escape after transmission to B57/5801-negative recipients. In the second case, they observed maintenance of CTL escape after transmission to recipients lacking B57/5801. A separate study examined this particular mutation and found no effect on viral fitness. They hypothesize that these two cases are extremes and that there is likely to be a broad spectrum of CTL escape mutations associated with greater or lesser degrees of constraint on viral replication.
These two papers demonstrate that intrapatient evolution of HIV driven by CTL escape does not necessarily translate into evolution of HIV at the population level, suggesting that some HIV CTL epitopes will be maintained in human populations.
Why does HIV-1 fail to replicate in simian cells?
HIV-1 fails to replicate in simian cells because of an early block in replication that the virus encounters after it has entered the cell. The block exists in cells derived from several nonhuman primate species, including rhesus macaques, which limits the usefulness of this species as a vaccine or treatment model for human AIDS. Previous coinfection and heterokaryon experiments have suggested that the block in replication is caused by a dominant inhibitory cell factor or activity.
A group led by Joseph Sodroski (Dana-Farber Cancer Institute and Harvard Medical School, Boston) has identified TRIM5-α, a component of cytoplasmic bodies, as the blocking factor (Nature 427:848; 2004). Using cells stably expressing TRIM5-α variants, they found that the human TRIM5-α protein was less effective in suppressing HIV-1 and SIVmac infection than was rhesus monkey TRIM5-α. This agrees with previous findings that suggested that HIV-1 capsids bind the Old World monkey restriction factor more efficiently than do SIVmac capsids. Sodroski and colleagues hypothesize that each virus has evolved in its natural host to achieve an acceptably low level of TRIM5- α interaction, and that vigorous, detrimental capsid disassembly may result when HIV-1 capsids encounter more effective TRIM5-α proteins, like those expressed in simian cells.
Why is it important to understand the early species-specific restrictions to HIV-1 replication? The researchers hope that the elucidation of TRIM5-α protein blocks will suggest approaches to the development of animal models of HIV-1 infection. They also suggest that insight into the HIV-1 uncoating process, a so far poorly understood aspect of the retroviral life cycle, may reveal intervention targets.
*Roberto Fernandez-Larsson, Ph.D., is the IAVI Report Web editor