After deposition of the virus on the recipient mucosa, the outcome is affected by properties of the virus: its retention of infectivity while traversing the mucus and extracellular matrix, its affinity for entry receptors, the fusogenicity of its Env protein, and the efficiency of its interaction with dendritic cells (DCs) that can promote virus spread to, and amplification in, CD4+ T cells, locally and possibly at distant sites (Figure 1) [8,9]. Superimposed upon this, there are likely to be strong selective pressures in the recipient at later steps, determining which virus takes over in the newly infected host (Table 1).
Figure 1. Early Events during Sexual Transmission of HIV
From top to bottom: The epithelial lining of the vagina forms an efficient barrier to viral penetration when intact. Cervical mucus may serve to strengthen this barrier by physically trapping virions . HIV crosses the epithelial barrier either because of epithelial damage (e.g., microabrasions and traumatic breaches or lesions caused by STDs), or capture by intra-epithelial DCs that convey the virus to target cells deeper in the mucosa . In the lumen of the vagina, continuous with the cervical canal, virions with two kinds of tropism are illustrated: (i) X4 virus (orange) uses the co-receptor CXCR4 (rarely found early after transmission) and (ii) R5 virus (green) utilizing the co-receptor CCR5 (preferentially found early after transmission). Why R5 virus comes to dominate in the newly infected host is not known; it may reflect preferential amplification at a stage after transmission (not shown) . To the left, an R5 virion is shown bound to an embedded DC, which has CD4, CCR5, and C-type lectin receptors on its surface, all of which can interact with the surface glycoprotein of the virus. The DC may merely capture X4 or R5 virus and carry it across the epithelial barrier or get infected by R5 virus and produce progeny virus (virus budding from the cell surface is shown as half-circular sections studded with grey Env spikes) . To the right, an R5 virion binds to and infects a T helper lymphocyte, which has both CD4 and CCR5 on its surface. Virus that has penetrated into the epithelium is also shown to infect a macrophage. Arrows indicate how virus infects the first target cells and how progeny virus or DCs then migrate via the afferent lymphatics to reach the lymph nodes. Here, further amplification occurs in an environment rich in CD4+ target cells. From there, new generations of progeny virus cascade to the next level of lymphatic tissue. The gut-associated lymphoid tissue provides an important reservoir of susceptible cells that the virus rapidly decimates (not shown). Ultimately, the virus disseminates via efferent lymphatics and blood to spleen, brain, liver, and lungs.
(Illustration: Courtesy IAVI Report, Volume 8, May–August 2004).
STDs make recipients more susceptible by breaking down the mucosal barrier in the case of genital ulcer disease and by increasing the number of susceptible cells in the mucosa through inflammation. Bacterial vaginosis—the colonization of the vagina by anaerobic bacteria—may further enhance the infectivity of incoming virus by raising the pH of the vaginal fluid: a higher pH would lead to slower virus inactivation and more efficient Env-mediated fusion [3,4]. Male susceptibility can be reduced by two-thirds through adult circumcision . It remains to be seen whether this is a direct effect on the number of target cells, in which the prepuce is rich, or an indirect effect on STD susceptibility and inflammation.
Newly transmitted viruses are likely to be more closely related to viruses that vaccines must protect against than later-stage viruses. Such early virus has been suggested to have distinct features. Early in infection, recipients appear to show much less viral diversity than the average infected person [11,12]. Derdeyn et al. investigated eight newly infected people from a cohort of more than 1,000 continual exposures among discordant couples. These recipients harbored HIV strains (seven clade C and one clade G) with notably short V1 and V2 variable regions of the viral envelope glycoprotein gp120, which therefore had relatively few glycosylation sites. This could affect the recognition of the Env complex by neutralizing antibodies. Indeed, virus isolated from the recipient showed greater sensitivity to neutralization by sera from the transmitting individual than did virus from the transmitter . The explanation may be either that neutralization-sensitive variants with more accessible receptor-binding domains pre-exist in the transmitter and are selectively transmitted, or that in the absence of neutralization pressure in the new host variants like this rapidly arise and expand.
However, such Env-selection does not seem to occur in clade-B transmission in intravenous-drug-abusing or homosexual cohorts . It is uncertain whether this discrepancy would relate to modes of transmission, HIV subtypes, or viral properties that evolve as the proportion of acutely infected individuals changes in the course of the epidemic . This is a topic of intensifying study that may shed new light on viral transmissibility.
Studies of highly exposed uninfected men from a cohort in Amsterdam failed to identify a unifying explanation for what prevented infection . Different host factors may contribute to resistance to HIV-1 infection, including innate immunity. Lymphocytes from some of the men showed reduced R5 HIV infection in vitro due to autocrine secretion of CCL chemokines. Lymphocytes from other seronegative persons in the cohort also showed poor proliferative responses in vitro. A subset of individuals had low numbers of memory effector T cells and a low activation level of CD4+ T cells, thereby presenting few target cells for the virus . The same magnitude and breadth of HIV-specific cytotoxic T cell responses were detected among exposed people whether they remained uninfected or later seroconverted . Qualitative differences between the cellular immune responses may nevertheless render some protective and others merely indicative of exposure. This is another very active area of investigation that may define immune correlates of protection against HIV infection.