Secondary[Acquired] Immunodeficiency states

may arise as complications of :- infections ; malnutrition ; aging ; or side effects of immunosuppression, irradiation , chemotherapy.

Acquired Immunodeficiency Syndrome (AIDS) : caused by retrovirus Human Immunodeficiency Virus

(HIV). characterized by profound immunosuppression that

leads to opportunistic infections, secondary neoplasms, and neurologic manifestations.

The virus is transmited via:

1. Unprotected sex with someone who is infected. 2. Transfusion of contaminated blood or blood products ; skin grafts or organ transplants taken from someone who is infected. 3. From a mother who is infected to her baby , this can occur during pregnancy, at birth , and through breast feeding. 4. Sharing unsterilized injection equipment that has previously been used by someone who is infected as in drug addicts.

Properties of HIV: HIV is retrovirus ( RNA containing virus ) that can

convert its genetic material into DNA by means of enzyme reverse transcriptase which enables it to become integrated into DNA of its host cells.

Two genetically different but related forms of HIV, called HIV-1 and HIV-2.

Structure of HIV: HIV virion is spherical and contains a cone-shaped core

surrounded by a lipid envelope derived from the host cell membrane .

The virus core contains: (1) major capsid protein ( p24 ). (2) nucleocapsid protein ( p7/p9 ). (3) two copies of genomic RNA. (4) three viral enzymes (protease , reverse transcriptase , and integrase).

p24 is the most readily detected viral antigen and, is the target for antibodies that are used for diagnosis of HIV infection.

The viral core is surrounded by a matrix protein called p17, which lies underneath the virion envelope.

Studding the viral envelope are two viral glycoproteins ( gp120 and gp41 ) which are critical for HIV infection of cells.

HIV- structure

Pathogenesis of HIV Infection and AIDS: there are two major targets of HIV infection: immune system and central nervous system.Immune system:- This results from infection and severe loss of

CD4+ T cells as well as impairment in function of surviving CD4+ T cells.

macrophages and dendritic cells are also targets of HIV infection.

HIV envelope contains two glycoproteins, surface ( gp120 ) that is non-covalently attached to transmembrane protein ( gp41 ).

The initial step in infection is binding of gp120. This binding leads to a conformational change that

results in formation of a new recognition site on gp120 for coreceptors CCR5 ( on macrophage ) or CXCR4 (on CD4+ T cells ).

The next step involves conformational changes in gp41 , these changes result in insertion of a fusion peptide at tip of gp41 into cell membrane of target cells .

After fusion, the virus core containing HIV genome enters cytoplasm of cell.

Once internalized, the RNA genome of virus undergoes reverse transcription, leading to formation of cDNA (proviral DNA) .

In quiescent T cells, HIV cDNA may remain in cytoplasm. In dividing T cells, the cDNA , enters the nucleus and

is then integrated into host genome. After this integration, the provirus may remain locked

into chromosome for months or years, and hence the infection becomes latent.

Alternatively, proviral DNA may be transcribed, with formation of complete viral particles that bud from cell membrane.

Such productive infection, when associated with extensive viral budding, leads to cell death.

Early in course of HIV infection, the immune system can replace the dying T cells.

Later in course of disease, renewal of CD4+ T cells cannot keep up with loss of these cells.

Despite the fact that macrophages allow viral replication, they are quite resistant to cytopathic effects of HIV, in contrast to CD4+ T cells. Thus, macrophages may be reservoirs of infection.

two types of dendritic cells are also targets of HIV infection: mucosal and follicular dendritic cells.

patients with AIDS also display profound abnormalities of B-cell function

Central Nervous System: It is a major target of HIV infection. Macrophages and microglia (cells in central nervous

system that belong to monocyte and macrophage lineage) are predominant cell types in brain that are infected with HIV.

HIV is carried into brain by infected monocytes.

Natural History of HIV Infection: Three phases recognized:-(1) Early , acute retroviral syndrome.(2) Middle, chronic phase.(3) Final , full-blown AIDS. Early , acute retroviral syndrome ( phase 1): high level of virus production, viremia, and

widespread seeding of lymphoid tissues. however, is readily controlled by development

of antiviral immune response. Clinically: nonspecific symptoms, including sore throat,

myalgia , fever, rash, weight loss, and fatigue, resembling a flulike syndrome.

Middle chronic phase ( phase 2 ): represents a stage of relative containment of virus,

associated with period of clinical latency. The immune system is largely intact, but there is

continuous HIV replication, predominantly in lymphoid tissues, which may last for several years.

Patients are either asymptomatic or develop persistent generalized lymphadenopathy.

Final phase ( phase 3 ), full-blown AIDS : Its progression to AIDS, characterized by a breakdown

of host defense, a dramatic increase in plasma virus, and clinical disease.

Typically the patient presents with long-lasting fever (>1 month), fatigue, weight loss, and diarrhea.

After a variable period: serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (grouped under the AIDS indicator diseases ), and the patient is said to have developed AIDS.

Clinical Features of AIDS: Opportunistic infections: account for the majority of deaths in patients with AIDS. Approximately 15% to 30% of HIV-infected people

develop pneumonia caused by opportunistic fungus P. carinii .The risk of developing this infection is extremely high in individuals with fewer than 200 CD4+ cells/µL.

other opportunistic infections are caused by Candida, cytomegalovirus, atypical and typical mycobacteria, Cryptococcus neoformans, Toxoplasma gondii, and herpes simplex virus.

Neoplasms : Kaposi sarcoma (KS) ; non-Hodgkin B-cell lymphoma ;

cervical cancer in women ; and anal cancer in men. It is estimated that 25% to 40% of HIV-infected

individuals will eventually develop malignancy. KS is composed of mesenchymal (spindle) cells that

form blood vessels; the proliferation of these cells is driven by a variety of cytokines and growth factors that are derived from tumor cells , and from HIV-infected T cells. it is strongly linked to infection of tumor cells by KS-associated herpesvirus (KSHV).

Central nervous system: 90%of patients demonstrate some form of neurologic

involvement at autopsy ; and 40% to 60% have clinically manifest neurologic dysfunction.

These include : self-limited meningoencephalitis ; aseptic meningitis ; vacuolar myelopathy ; peripheral neuropathies ; and most commonly a progressive encephalopathy designated clinically as (AIDS-dementia complex ).

Morphology: Biopsy specimens from enlarged lymph nodes in

early stages of HIV infection reveal marked follicular hyperplasia.

With disease progression, B-cell proliferation subsides and gives rise to severe follicular involution. The follicles are depleted of cells. The germinal centers may become hyalinized. These lymph nodes are atrophic and small and may harbor numerous opportunistic pathogens.

Lymphoid depletion is not confined to lymph nodes; in later stages of AIDS, the spleen and thymus also appear to be "wastelands."

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