Pathophysiology transmission and progression of HIV disease

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The gut, more than any other organ in the body, plays a critical role in the vertical transmission and progression of HIV infection. This reflects not only its nutritional function but also its central activity in immune programming and regulation. More than half the body's total lymphoid tissue is found in the bowel; as HIV infects lymphocytes with CD4 or other co-receptors, this makes the bowel an ideal target for primary infection and a site for viral replication and seeding.

Intestinal lymphoid tissue is organized into distinct structures including the tonsils, Peyer's patches (mainly in the ileum) and mesenteric lymph nodes, and is also diffusely spread throughout the mucosal epithelium and lamina propria. Activation of both the organized and diffuse elements of the gut immune system depends on presentation of antigens to T and B lymphocytes lying beneath the epithelium. M

cells are specialized epithelium found in the follicle-associated epithelium (FAE) that overlies Peyer's patches in the small intestine and lymphoid follicles in the rectum, and are also found in rich supply in the tonsils. These are capable of transporting macromolecules and micro-organisms, including viruses such as polio, to macrophages or possibly dendritic cells in the lamina propria. These latter cells are the professional antigen-presenting cells that facilitate presentation of antigens to activated and possibly non-activated T cells. However, intestinal epithelium itself can also generate antigen-specific responses and may be able to function as antigen-presenting cells. Complementing these responses are intraepithelial lymphocytes, interspersed throughout the mucosa, that produce cytokines which support humoral and cell-mediated responses. Finally, the lamina propria throughout the gut contains the bulk of the immune effector cells including T and B lymphocytes, plasma cells, macrophages, mast cells and some eosinophils and neutrophils.

Primary infection with ingested HIV depends on the virus gaining access to the lamina propria, where, in early infection, it replicates primarily in lymphocytes.1,2 The exact mechanism for entry to the lamina propria is not fully understood, but may be through a variety of routes, and is likely to be a complex process modified by viral characteristics, gut mucosal receptors and the factors that promote or impede the interaction.

Direct passage through disruptions in mucosa or between immature mucosal junctions is possible. However, longitudinal gut permeability studies in children born to HIV-infected mothers do not support this mechanism.3 Rather, increased permeability, without clinical symptoms, may be present soon after children become infected.

Recent work shows that gut mucosa does not express the familiar CD4 binding sites that the HIV-1 gp120 protein commonly uses for attaching to and thereby infecting mononuclear cells.4 Rather, early infection is dependent on HIV strains binding to alternative sites, namely the primary receptor galactosyl ceramide (GalCer) and the CCR5 co-receptor, which are expressed on upper gastrointestinal epithelium.5 This is supported by the observation that HIV-1 isolates from acutely infected persons are predominantly R5 viruses, i.e. macrophage-tropic HIV that require CCR5 for cell entry (in contrast to R4 viruses, which are lymphocyte-tropic requiring the CXCR4 chemokine co-receptor).6 Once attached, the virus is probably translocated across the epithelial cell and presented to T lymphocytes that express the same CCR5 co-receptor. The lamina propria now becomes a potent site for viral replication. M cells, in mouse and rabbit ex vivo systems, can transport HIV-1 to mononuclear cells, but human M cells have not been shown to take up and transport HIV in the same way.7

The gut has a number of defense mechanisms against primary infection apart from maternal factors. The rapid passage of ingested amniotic fluid or maternal blood limits contact time with M cells expressed on the surface of the tonsils. Gastric acid would normally inhibit HIV in the stomach, but this is reduced in neonates and young infants. Mucin produced by goblet cells and the rapid turnover of the intestinal mucosa provide additional mechanical barriers to HIV attachment.

However, mother-to-child transmission of HIV through breast feeding depends on a number of risk factors other than the susceptibility of the gut to HIV. Increased viral load in breast milk is correlated with high plasma viral load and decreased CD4 count in the mother, and is associated with higher transmission.8-10 These conditions are found in the early stages of new infection or in advanced disease. It is not clear, however, whether it is cell-associated or cell-free virus that is more important for transmission. Other breast-milk factors such as HIV-1-specific IgG and secretory leukocyte protease inhibitor (SLPI) have HIV-1 inhibitory activity in vitro.11 SLPI acts on the target cell rather than the virus and inhibits internaliza-tion of HIV-1 rather than initial binding.12

Infant feeding practices may significantly influence the way in which these non-intestinal factors interact: exclusive breast feeding results in a greater volume of milk being ingested and hence increases the HIV load presented to the infant gut. However, it also increases the protective breast-milk factors reaching the infant and that promote the development and maintain the integrity of the mucosa and which may have direct anti-HIV effects.13 Exclusive breast feeding is associated with fewer breast health problems, e.g. clinical and subclinical mastitis that are associated with increased breast-milk viral load.14 Infant feeding practices also contribute to the establishment of different enteric microflora that might significantly affect the priming or responses of intestinal lymphoid cells or dendritic cell.15-17 This could, theoretically, modify adherence or facilitate infection of HIV, although this interesting concept has not been explored to date. Innate responses such as lactoferrin and lysozymes that are secreted by exocrine glands onto mucosal surfaces are bactericidal, but their protective capacity in HIV is unknown. There is also renewed interest around secretory IgA and IgM that can inhibit transcytosis of HIV-1 across enterocytes in in vitro models.18,19 Passive immunization of macaque monkeys with monoclonal antibodies against the HIV-1 gp120 protein, given either orally or applied locally, protected against mucosal challenges with HIV-1.20 This raises the possibility of a vaccine strategy, similar to that used against hepatitis B, of combining active and passive immunization to induce effective mucosal protection against HIV-1.

Once HIV infection is established the gut serves as a major reservoir for viral amplification. CD4 lymphocytes in the lamina propria are infected and progressively depleted;21 this precedes the eventual decrease in CD4 counts in the peripheral circulation and other sites.22,23 IgA-secreting plasma cells, especially the IgA2 subclass, are lost early in disease, resulting in reduced secretory IgA, thereby predisposing the gut to infection with enteric pathogens.24-27 Responses to oral vaccines may also be impaired, raising concern about the effectiveness of putative rotavirus vaccines in areas of high HIV seroprevalence.28 Local cytokine responses have been extensively reported, although it is still not entirely clear whether they influence the development of AIDS or HIV

enteropathy or are simply the consequence of the latter.29,30 These responses may be the consequence of opportunistic infections or the direct effect of HIV on the mucosa.

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New Mothers Guide to Breast Feeding

New Mothers Guide to Breast Feeding

For many years, scientists have been playing out the ingredients that make breast milk the perfect food for babies. They've discovered to day over 200 close compounds to fight infection, help the immune system mature, aid in digestion, and support brain growth - nature made properties that science simply cannot copy. The important long term benefits of breast feeding include reduced risk of asthma, allergies, obesity, and some forms of childhood cancer. The more that scientists continue to learn, the better breast milk looks.

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