Human Immunodeficiency Virus pdf - D. Entedhar

Human Immunodeficiency Virus

(HIV)

/ اﻟﻤﺮﺣﻠﮫ اﻟﺜﺎﻟﺜﮫ

ﻓﺎﯾﺮوﺳﺎت

د. اﻧﺘﻈﺎر ﻋﻼوي ﺟﻌﻔﺮ / ﻓﺮع اﻻﺣﯿﺎء اﻟﻤﺠﮭﺮﯾﮫ / ﻛﻠﯿﮫ اﻟﻄﺐ / ﺟﺎﻣﻌﮫ ذي ﻗﺎر

PhD. M.Sc. Microbiology

Classification

Human immunodeficiency virus (HIV) is a a Lentivirus , a sub family of

Lentiviridae in the family Retrovirus that causes

Acquired immunodeficiency syndrome (AIDS).

HIV is this family includes the viruses known for: (i) Poor host immune
responses, (ii ) Latency. (iii ) Persistent viremia and (iv) Infection of the central

nervous system.

Morphology

HIV is a spherical, enveloped virus, which measures up to 120 nm in diameter

(See-Fig). HIV, is an enveloped RNA viruses, possessing an RNA-dependent DNA

polymerase called Reverse transcriptase. It has a unique three-layered

structure:

(i) The innermost genome layer, (ii) Middle cone shaped nucleocapsid

(iii) An outer membrane of glycoprotein surrounded by lipoprotein envelope.

Viral genome

HIV genome is most complex of human retroviruses. The genome consists of two

identical copies of single-stranded positive-sense RNA genome. The HIV contains

three major genes gag , pol , and env , characteristic of all retroviruses. All these

genes encode for the structural proteins.

The gag gene encodes for internal capsid and matrix “core” proteins (p15, p18,

and p24).

Of these three proteins, p24 is the major antigen, which is demonstrated in

serum of HIV patients during the early stage of infection and persists till the

appearance of serum antibodies. Detection of p24 antigen in serum, therefore, is

of diagnostic value.

The pol gene encodes for several proteins, including the enzymes reverse

transcriptase, integrase, and protease. The enzyme reverse transcriptase

synthesizes DNA by using the genome RNA as a template. The enzyme integrase

integrates the viral DNA into the cellular DNA, and the enzyme protease cleaves

various viral precursor proteins.

The env gene codes gp160, a precursor glycoprotein that is split to form two

envelope glycoproteins, gp120 and gp41, which form the surface spikes and

transmembrane tissue proteins, respectively.

HIV also consists of six other regulatory genes (tat , rev , nef , vif , and vpr).

These genes encode several proteins, which are essential for transcription and

invasion of virion into host cells.

tat gene is the most important one, which encodes a protein called Tat protein

that facilitates viral gene transcription. Tat protein along with other HIV-
encoded regulatory protein called Nef suppresses the synthesis of class I MHC

proteins thereby reducing the ability of cytotoxic T cells to kill the HIV-infected

cells.

Nucleocapsid: The viral genome is surrounded by a nucleocapsid consisting of

proteins. Three enzymes are located in the nucleocapsid:

(i) Reverse transcriptase, which transcribes the RNA genome into the proviral

genome. (ii) Integrase and (iii) Protease.

Viral replication

The virus binds to the CD4 proteins on the cell surface (T lymphocytes and

macrophages) with the help of its gp120 envelope protein (See-Fig). This

protein also interacts with chemokine receptors on the cell surface including the

CXCR4 and CCR5, which are essential for entry of HIV into CD4 cells.

Then gp41 of the virus mediates fusion of the viral envelope with the cell

membrane followed by entry of the virus into the cell.

Once inside the cell, after uncoating, the virion RNA-dependent DNA

polymerase transcribes the genome RNA into double-stranded DNA, which

subsequently integrates with the host cell DNA. Integration is mediated by the

viral enzyme integrase. The host cell RNA polymerase transcribes the viral

mRNA from the proviral DNA.

The viral mRNA encodes several proteins, protease to form the main core

protein (p24), the matrix protein (p17), and several smaller proteins. Such as

reverse transcriptase, integrase, and protease.

The immature virions containing the precursor polyproteins are assembled in

the cytoplasm, and cleavage by the viral protease occurs as the immature virion

buds from the cell membrane, resulting in the production of mature infectious

HIV.

Pathogenesis and Immunity

HIV is primarily a sexually transmitted pathogen transmitted by high-risk

behaviors, such as unprotected intercourse, male homosexual intercourse, and

also by intravenous (IV) drug abuse.

he tropism of the HIV for CD4-expressing T-cells and macrophages is the

principal determinant of the pathogenicity of HIV.

The CD4 antigens act as receptors for HIV. The virus infects helper T cells and
kills them, resulting in HIV-induced immunosuppression, leading to full-blown

AIDS—a key feature of the pathogenesis of HIV infection. This makes the patient

most susceptible to opportunistic infections and certain cancerous conditions,

such as Kaposi’s sarcoma and lymphoma. However, the virus does not directly

cause any tumor, because HIV genes are not found in these tumor cells.

The virus replicates continuously in the lymph nodes, thereby releasing the

virions and infected T cells into the blood.

During the course of infection, the virus causes a drastic reduction in the number

of CD4 T cells, which may occur due to direct HIV mediated cytopathic effect,

virus specific immune response, or apoptosis induced by viral proteins.

The deficiency or reduction of CD4 T cells leads to depression of cellular immune

response and impairment of humeral responses. The reduction of CD4 T cells is

responsible for producing delayed-type hypersensitivity reaction that leads to

opportunistic infections caused by many opportunistic pathogens.
Clinical Syndromes

The course of untreated HIV infection is usually 10 ears or longer. The disease

progresses through the stages of

(a) Primary infection (flu like disease).

(b) Dissemination of virus to lymphoid organs.

(d) A late stage of profound immunosuppression known as full-blown Acquired

Immune Deficiency Syndrome (AIDS).

Acute HIV infection

Is characterized by rapid rise in plasma viremia with a concomitant drop in CD4

count after an incubation period of 3–6 weeks. The symptoms of HIV are

nonspecific and include low-grade fever, fatigue, malaise, rash, headache, and

lymphadenopathy; spontaneous resolution may occur within weeks.

Asymptomatic HIV infection

This period is followed by an asymptomatic or clinically latent stage during

which the patient continues to remain asymptomatic for several months to years.

This stage is characterized by a low level of viral replication and a gradual fall in

CD4 count. The serum is positive for HIV antibodies in these patients. Another
characteristic of the stage of latency is persistent generalized lymphadenopathy,

which may last for several years or a period of asymptomatic infection. During

this stage, virus continues to replicate in the lymph node.

Acquired Immune Deficiency Syndrome (AIDS)

Is characterized by lymphadenopathy and fever. AIDS is the end-stage disease of

the HIV infection. It denotes the irreversible breakdown of immune system of the

host, making the infected host highly susceptible to a wide range of progressive

opportunistic infections such as tuberculosis, Pneumocystis carinii pneumonia,

toxoplasmosis, cryptococcal meningitis or unusual malignancies, such as

Kaposi’s sarcoma, non- Hodgkin’s lymphoma, Hodgkin’s lymphoma, cervical

cancer, and Burkitt’s lymphoma.

AIDS is characterized by deterioration of immune response as evidenced by CD4

T cell decrease response. The onset of clinical manifestations correlates with:

A reduction in number of CD4 T cells to less than 450/L.

Increased level of virus in the blood.

Presence of p24 antigen in the blood.

Transmission of infection

HIV is primarily a human infection. Humans infected with HIV and AIDS are the

reservoir of infection. The high titer of HIV is found in the body fluids including

blood, semen, and vaginal secretions of the infected people; hence these are

important sources of infection. HIV transmission occurs in following ways

Sexual transmission.

Transmission by blood transfusion.

Parenteral transmission occurs largely among IV drug users through the

use of contaminated needles.

Mother-to-child transmission: can occur by vertical transmission

through the placenta or through the amniotic membrane or by perinatal

transmission during delivery through infected birth canal.

Breast feeding

Laboratory Diagnosis

Specimens: these include serum and plasma for HIV serology and lymphocytes

for isolation of HIV.

• Serodiagnosis: Detection of specific antibodies to envelope glycoproteins

gp41, gp120, and gp160 and to viral core p24 antigens using ELISA

assay. The level of these antibodies is demonstrated in most individuals

within 6–12 weeks after infection and in all the individuals within 6

months of infection.

Molecular Diagnosis: The circulating virus count (viral load) is

determined by means of quantitative RT-PCR. It can also be used to

monitor the success of therapy with RT and protease inhibitors

Treatment

There is no cure for HIV infection. However, effective antiretroviral drugs (ARVs)

can control the virus and help prevent onward transmission to other people.

The anti-HIV drugs can be broadly classified as:
(a) Nucleoside analoge reverse transcriptase inhibitors (NRTIs) e.g Zidovudine,

Didanosine, Zalcitabine and Lamivudine.

(b) Nonnucleoside reverse transcriptase inhibitors (NNRTIs) e.g Nevirapine,

Delaviridine, Efavirenz.

Therapy with combination of Highly active antiretroviral therapy, referred to

as HAART, is effective in inhibition of HIV replication.

HAART has improved efficacy of the therapy, minimized toxicity following

therapy, and delayed emergence of drug resistance. It is usually recommended to

initiate double and triple drug therapy with two NRTIs Or two NRTIs an NNRTI

or a protease inhibitor.