infection The pathology of HIV disease results from either tissue destruction by the virus itself or the host’s response to virus-infected cells. In addition, HIV can induce an immunodeficient state that leads to opportunistic diseases that are rare in the absence of HIV infection. The progression from HIV infection to AIDS develops in 50 percent of HIV-infected individuals in an average of 10 years, and, if untreated, it is uniformly fatal, generally within 2 years of diagnosis. However, there is a significant fraction (about 10 percent) of HIV infected individuals who have not developed AIDS after 20 years. Development from HIV infection to end-stage AIDS progresses through several phases (Figure 1).

Fig1. Typical time course of human immunodeficiency virus (HIV) infection.

1. Initial infection: After the acquisition of HIV, the initially infected cells are generally macrophages within the genital tract. From this initial localized infection, HIV disseminates via the blood, and virus may then localize in dendritic cells throughout the lymphoid tissue. From the surface of follicular dendritic cells, HIV can then infect CD4+ lymphocytes moving through the germinal centers of lymph nodes. This process creates a reservoir of chronically HIV infected cells within the lymphatic tissue throughout the body. Some individuals are resistant to some variants of HIV-1 due to a deletion in the gene that encodes the coreceptor (C-C chemokine receptor type 5, or CCR5) for the virus.

 2. Acute phase viremia: Several weeks after the initial infection with HIV, one-third to two-thirds of individuals experience an acute dis ease syndrome (also referred to as the primary infection) similar to infectious mononucleosis. During this period, there is a high level of virus replication occurring in CD4+ cells. Large amounts of virus and capsid protein (CA antigen) are present in the blood, but circulating antibody does not appear until 1 to 10 weeks after the initial infection (seroconversion). During this window of time, antibody tests will not identify HIV-infected people. Lymph nodes also become infected during this time and later serve as the sites of virus persistence during the asymptomatic period.

 3. Latent period: The acute phase viremia is eventually reduced significantly with the appearance of a HIV-specific cytotoxic T-lymphocyte response, followed by a humoral antibody response. A clinically asymptomatic or “latent” period lasting from months to many years follows the acute infection. During this latent period, the majority (90 percent) of HIV proviruses are transcriptionally silent, so that only 10 percent of the cells containing integrated HIV DNA also contain viral mRNA or viral proteins. A constant level of virus and virus-infected cells is maintained by a combination of replacement of the CD4+ cells killed by HIV infection with cells newly produced in lymphoid organs and the subsequent infection of these new cells with progeny virus. There are transient peaks of viremia that are often correlated with stimulation of the immune system by infection with other pathogens or by immunization. Although there is continuous loss of those CD4+ cells in which HIV is replicating, active replacement through stem cell multiplication compensates for this loss, and the CD4+ count declines only slowly over a period of years. In addition, the host immune response is still sufficiently effective to maintain a relatively stable, low level of virus production. It has been estimated that 1011 virions and 10⁹ CD4 T cells are produced each day. Virus isolated during this period is also less cytopathic for CD4+ cells and replicates more slowly than does virus isolated later during symptomatic AIDS. Despite the nearly normal levels of CD4+ cells, however, impairment of T-cell responses to specific antigens is evident. The infection remains relatively clinically asymptomatic as long as the immune system is functional. The actual level of virus replication in peripheral blood cells varies greatly among patients, and those with a higher steady-state viral load progress more rapidly to symptomatic AIDS and death.

4. Clinical complications of HIV infection during the latent period: During this period (of variable length but lasting on average about 10 years), there are multiple, nonspecific conditions, such as persistent, generalized lymphadenopathy (swollen lymph nodes); diarrhea; chronic fevers; night sweats; and weight loss. The more common opportunistic infections, such as herpes zoster and candidiasis, may occur repeatedly during this period as well as when patients progress to AIDS.

5. Progression to AIDS: The progression from asymptomatic infection to AIDS is not sudden but, in fact, occurs as a continuum of clinical states. A number of virologic and immunologic changes occur that affect the rate of this progression. For example, coinfection with a number of the herpesviruses, such as human herpesvirus type 6, can transactivate transcription from the silent HIV provirus, increasing HIV replication. Any stimulation of an immune response causing activation of resting T cells also activates HIV replication. Not only does this increase the number of infected CD4+ cells, but it also increases the opportunity to create generations of virus mutants. Eventually, a more highly cytocidal, more rapidly multiplying variant appears. This transition is also often accompanied by the appearance of a CXCR4-tropic virus variant, whereas the infecting variants tend to be CCR5 tropic. [Note: The CXCR4 receptor is one of several chemokine receptors that HIV isolates can use to infect CD4+ T cells.] In addition, these variants are often highly syncytium-inducing, promoting fusion between infected and previously uninfected cells. T cell precursors in the lymphoid organs are also infected and killed, so the capacity to generate new CD4+ cells is gradually lost. The capacity to contain the infection is further compromised by the appearance of HIV mutants with altered antigenic specificity, which are not recognized by the existing humoral antibody or cytotoxic T lymphocytes. The eventual result of these accumulating, interacting factors is an increasingly rapid decline in CD4+ count, accompanied by loss of immune capacity. With the CD4+ count falling below 200/μl and the appearance of increasingly frequent and serious diseases and opportunistic infections (“AIDS defining illnesses”), the patient is said to have AIDS.

6. End-stage AIDS: Nearly all systems of the body can be affected as a result of HIV infection, either by HIV itself or by opportunistic organisms. The weakening immune system leads to many complications, including malignancies.

a. Spread of HIV to additional body sites: Cell types other than CD4+ lymphocytes can be infected by HIV. Infection of these cells produces some of the additional manifestations of end stage disease. Chief among these are infected cells of the monocyte-macrophage lineage, which are not killed as rapidly as CD4+ T cells and can transport the virus into other organs (Figure 2). For example, microglia are the HIV-infected cells present in brains of patients with AIDS encephalopathy, which typically evolves over a period of 1 year, with gradual deterioration resulting in severe dementia. This appears to be unrelated to CD4+ depletion but, rather, to an expanded tropism of variant HIV. The basis for damage to neuronal cells is not known, however. Similarly, the wasting syndrome seen in late stages of AIDS probably relates to HIV-infected macrophages being induced to produce various cytokines, especially tumor necro sis factor. HIV infection of blood cell progenitors in the bone marrow leads to the anemia seen in most AIDS patients.

Fig2. Pathogenesis of human immunodeficiency virus (HIV).

b. Opportunistic infections in AIDS: Multiple recurrent bouts of infections with fungi, bacteria, and viruses occur as the CD4+ cell count declines (Figure 3). For example, the nervous system can be the site of opportunistic infections with Toxoplasma, Cryptococcus, JC virus, and mycobacteria. The eye can be infected with HIV, but also with opportunistic agents, the most prominent of which is cytomegalovirus (CMV), a cause of retinal destruction. The lungs are also primarily affected by opportunistic infections, P. jirovecci pneumonia being one of the most common. Mycobacterial infections are also a common problem in the lung. For example, currently, 30 percent of AIDS patients die from tuberculosis (see p. 186). Serious gastrointestinal (GI) tract illnesses are due to opportunistic pathogens, but these may be in concert with HIV infection. CMV colitis is a common problem, but HIV is often present as well. Protozoal parasitic diseases, as well as infections with gram-negative enteric bacteria are other sources of GI disorders. The immune deficiency also provides the opportunity for latent infections to recur repeatedly or to become chronic and spread extensively. Recurrent infections by Epstein-Barr virus (EBV), varicella zoster virus, human papillomavirus, and herpes simplex virus are common. Mucocutaneous candidiasis (for example, oral, esophageal, or vaginal) is an ongoing problem in AIDS patients as well. In fact, vaginal candidiasis is the most frequent reason HIV infected females seek medical attention. See Figure 3 for a summary of common AIDS-defining opportunistic infections.

Fig3. Pattern of opportunistic infections associated with declining CD4+ cell counts. CMV = cytomegalovirus; MAC = Mycobacterium avium complex; PJP = Pneumocystis jiroveci pneumonia; HIV = human immunodeficiency virus.

c. Malignancies associated with AIDS: A number of malignancies commonly arise in HIV-infected patients. The most characteristic neoplasm present in AIDS patients is KS, which involves skin, mucous membranes, and deep viscera. Various lymphomas, including those of the central nervous system (CNS), are also common. These are probably the result of the immune compromise and not HIV itself. KS has been associated with human herpesvirus, type 8 (HHV-8) as shown in Figure 4. In AIDS patients, body cavity lymphomas are also usually associated with HHV-8 infection, whereas many other lymphomas are EBV associated.

Fig4. Herpesvirus 8 virions (arrows) associated with Kaposi sarcoma.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم شؤون المعارف ينظم دورة متقدمة في تحقيق المخطوطات لملاكاته

قسم الشؤون الفكرية يصدر العدد العشرين من مجلة دراسات إفريقية

المجمَع العلمي يكرم الأساتذة المشاركين في مشروع الدورات القرآنية الصيفية في كربلاء

العتبة العباسية المقدسة تختتم فعاليات البرنامج المركزي الأسبوعي لمنتسبيها

المزيد

الآخبار الصحية

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ماذا يحصل لجسمك عند التوقف عن استخدام الزيت في الطهي؟

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المزيد

الآخبار التكنلوجية

زلزال أفغانستان يحصد أكثر من ألف قتيل.. ويدمر آلاف المنازل !

ناجٍٍ وحيد من انزلاق أرضي.. دمّر قرية سودانية بأكملها !

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ما السر وراء مشية إيلون ماسك الغريبة والسريعة ؟

المزيد

مواضيع ذات صلة

Transmission of HIV

HIV replication

Hepatitis D

Prevention and Treatment of hepatitis B

Differentiating Acute and Chronic Hepatitis and the Chronic Carrier State

Flaviviridae

Togaviridae

Caliciviridae

Picornaviridae

Laboratory Assays of Hepatitis B

Epidemiology of Hepatitis B

Hepatitis A