HIV/AIDS의 병태생리학

HIV는 일반적으로 무방비한 성관계, 수혈, 피하주사 바늘을 통해, 또는 산모부터 아기에게로 전파된다. HIV에 감염되면, 바이러스는 거의 모든 후천면역 반응에 관여하는 보조 T세포 안에서 증식하고 결국에는 이 세포를 파괴한다. 독감과 비슷한 질병의 초기 단계가 있고, 그 후에 무증상 단계인 잠복기가 있다. CD4 림프구 수가 1ml 혈액 당 200개 미만으로 줄어들 때, HIV 감염자는 세포 매개 면역이 결핍된 상태인 AIDS로 진행되고, 결과적으로 기회감염이나 특정 암에 대해 취약해진다.

Immunology

바이러스가 체내로 들어온 후 빠르게 증식하는데, 이로 인해 말초혈액에 바이러스가 많이 생긴다. 1차 감염 시, HIV 수는 혈액 1ml 당 수백만 입자에 다다른다.

이런 반응은 혈액을 순환하는 CD4+ T세포 수의 급격한 감소를 수반한다. 급성 바이러스 혈증은 HIV 감염세포를 파괴하는 CD8+ T세포의 활성화와, 그 후에 일어나는 항체 생산이나 혈청 변환과 관련되어 있다. 바이러스 수가 정점에 도달한 후 감소할 때, CD4+ T세포는 다시 증가하는데, 이 때 CD8+ T세포는 바이러스 수준을 조절하는데 중요하다. CD8+ T세포는 바이러스를 제거하지는 않지만, CD8+ T세포 반응이 잘 일어나면 질병의 진전을 늦출 수 있고, 더 나은 예후가 나타난다.

During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4⁺ T cell depletion, although apoptosis may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4⁺ T cell numbers.

Although the symptoms of immunodeficiency (characteristic of AIDS) do not appear for years after a person is infected, the bulk of CD4⁺ T cell loss occurs during the first weeks of infection, especially in the intestinal mucosa, which harbors the majority of the lymphocytes found in the body. The reason for the preferential loss of mucosal CD4⁺ T cells is that a majority of mucosal CD4⁺ T cells express the CCR5 coreceptor, whereas a small fraction of CD4⁺ T cells in the bloodstream do so.

HIV seeks out and destroys CCR5 expressing CD4⁺ cells during acute infection. A vigorous immune response eventually controls the infection and initiates the clinically latent phase. However, CD4⁺ T cells in mucosal tissues remain depleted throughout the infection, although enough remain to initially ward off life-threatening infections.

Continuous HIV replication results in a state of generalized immune activation persisting throughout the chronic phase. Immune activation, which is reflected by the increased activation state of immune cells and release of proinflammatory cytokines, results from the activity of several HIV gene products and the immune response to ongoing HIV replication. Another cause is the breakdown of the immune surveillance system of the mucosal barrier caused by the depletion of mucosal CD4⁺ T cells during the acute phase of disease.

This results in the systemic exposure of the immune system to microbial components of the gut’s normal flora, which in a healthy person is kept in check by the mucosal immune system. The activation and proliferation of T cells that results from immune activation provides fresh targets for HIV infection. However, direct killing by HIV alone cannot account for the observed depletion of CD4⁺ T cells since only 0.01–0.10% of CD4⁺ T cells in the blood are infected.

A major cause of CD4⁺ T cell loss appears to result from their heightened susceptibility to apoptosis when the immune system remains activated. Although new T cells are continuously produced by the thymus to replace the ones lost, the regenerative capacity of the thymus is slowly destroyed by direct infection of its thymocytes by HIV. Eventually, the minimal number of CD4⁺ T cells necessary to maintain a sufficient immune response is lost, leading to AIDS.

CD4 T-cell Death and Inflammation

Recent studies employed an ex vivo human lymphoid aggregate culture (HLAC) system formed with fresh human tonsil or spleen tissue to model molecular and cellular events in human tissues during in vivo HIV infection. These studies found that >95% of CD4 T cells die because of abortive HIV infection. These dying cells are resting and thus are nonpermissive for productive HIV infection. Full viral replication was limited to the ∼5% of activated CD4 T cells present in these tissues; these cells die by apoptosis. Abortive HIV infection occurs due to slowing of reverse transcription promoting cytosolic DNA accumulation. This viral DNA is sensed by gamma-interferon-inducible protein 16 (IFI16), which produces an innate immune response against the virus by activating caspase 1 in IFI16 inflammasomes and inducing pyroptosis, a highly inflammatory form of programmed cell death. These findings cast CD4 T-cell death during HIV infection in a different light. Rather than the virus playing a major role, it is the host response to viral DNA produced during abortive infection that triggers CD4 T-cell death. Further, these findings identify novel drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis.

Cells affected

The virus, entering through which ever route, acts primarily on the following cells:

• Lymphoreticular system:
  • CD₄+ T-Helper cells (main target cell)
  • Macrophages
  • Monocytes
• Certain endothelial cells
• Central nervous system:
  • Microglia of the nervous system
  • Astrocytes
  • Oligodendrocytes
  • Neurones – indirectly by the action of cytokines and the gp-120

The effect

Although the virus has cytopathic effects in productively infected cells, this effect may not directly contribute to HIV pathogenesis (see above). Importantly, the virus can remain inactive (latent) in these productively infected cells for long periods.

• CD4 T-cell depletion and chronic inflammation are the two signature events that drive HIV pathogenesis and progression to AIDS.
• Infection of the cells of the CNS cause acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. Later it leads to even AIDS dementia complex.
• The CD₄-gp120 interaction (see above) is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i. e. cytopathy.

See also

• Structure and genome of HIV
• HIV replication cycle
• HIV tropism