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The article discussed HIV transmission and possible therapeutic interventions...


Biology Articles » Virology » How Do Viral and Host Factors Modulate the Sexual Transmission of HIV? Can Transmission Be Blocked? » Establishment of Infection in the Vagina or Rectum at a Histological Level

Establishment of Infection in the Vagina or Rectum at a Histological Level
- How Do Viral and Host Factors Modulate the Sexual Transmission of HIV? Can Transmission Be Blocked?

Experiments using cervical explants indicate that an intact mucosal epithelium forms an impenetrable barrier to HIV [8]. It is difficult to judge whether the barrier is equally impenetrable and the trafficking of cells across it similar when the tissue is perfused by circulating blood in the living organism. But there appear to be additional impediments to HIV replication, since replication is restricted even when the mucosal layer is breached by microabrasions.

In macaque models of SIV infection, the viral dose is higher than in most human exposures, perhaps higher even than when the transmitter is at the peak of primary-infection viral load. However, in this model the first infectious events in the mucosa occur within hours. During the first days, there is some dissemination beyond the mucosa: this may be mediated through lymphovascular anastomoses or trafficking of the virus by DCs [9]. It usually takes 4–6 days for the infection to become systemic. The establishment of a productive infection in the animal seems to depend critically on the continual seeding from a founder population of infected, ostensibly resting, memory CD4+ T cells in the genital tract. From these, the infection further disseminates to local lymph nodes and then to secondary lymphatic tissue, eventually becoming systemic [16,17]. The escalation from one level to the next has been likened to a broadcast effect, each wave involving new bursts of amplification of the virus (Figure 1) [16,17]. Virus is found in the gut-associated lymphoid tissue by day 6–7, when only the rudiments of an SIV-specific immune response are detectable. Within 14 days of SIV infection, effector memory CD4+ cells in the intestinal lamina propria are selectively and permanently depleted [18]. It is plausible that many exposures to the virus that do not lead to established infections involve local, transitory viral replication. And when the infection does get established, scattered foci of founder cells arise from only a small fraction of the inoculum. The delay of up to six days before systemic replication, even in this high-dose model, and in spite of the rapid dissemination to draining lymph nodes, suggests that a crucial level of replication in local lymphoid tissues is required for establishment of infection. Below this level, the infection may abort. This scenario implies that prevention is still possible during a short period in which the virus is actively replicating. If this simian model accurately reflects the events in human transmission, it can help elucidate exactly what must be achieved in prevention.

Even though retroviral infection is seen as irreversible because of the integration of the pro-virus into the host-cell genome, the dynamic model of seeding and dissemination described above gives reason to modify that view: at the level of the organism, abortive HIV infections may be frequent. Sterilizing immunity would not need to achieve more than what hypothetically happens spontaneously in many cases when a seeding population is too small to sustain the cascading events. Consequently, there could be a window of opportunity early in infection for a potent, local, vaccine-induced immune response or a microbicide to prevent or dampen viral replication in the first host cells and thereby to increase the chances that subsequent immune mechanisms abort the nascent infection. This is also consistent with protection of macaques through systemic administration of inhibitors of reverse transcription or of entry (CCR5 ligand CMPD167), if treatment is started 24–48 hours after exposure to SIV or SHIV (HIV–SIV hybrids) and continued for 10–28 days [19,20].


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