1. Role of CD4+ T-lymphocytes in HIV infection:

• CD4+ T-cells are major target of HIV. This is because T-lymphocytes expresses CD4 molecules as receptor and CXCR4 as co-receptor for viral glycoprotein spike gp120 and gp41.

• CD4+ T –cells are the primary immune cell and is responsible for activation of macrophages for phagocytosis, B-cell for antibody production and secretion of cytokines.

• The results of viral infection causes depletion of CD4 T-cells.

• Most of the infected CD4+ T-cells are destroyed while few survive and revert into resting memory cells, which provide long term latency to HIV.

• Activation of memory T-cell release HIV viruses.

Causes of depletion of CD4+cells in HIV infection:

1. Virus replication
2. Syncytia formation
3. Cytotoxic T-cell lysis of infected CD4+T-cells
4. Antibody dependent cell mediated cytotoxicity (ADCC)
5. Natural killer cell mediated phagocytosis

2. Role of macrophages and monocytes in HIV infection:

• Macrophages and monocytes bearing CD4+ molecules and CCR5 on surface are also targeted by HIV.

• These macrophages and monocytes are the principle cells by which HIV enters to Central Nervous system (CNS) by crossing blood brain barrier (BBB).

• Macrophages and monocytes are affected when the count of CD4+ T- cell deletes rapidly.

• The infected monocytes secretes cytokines in the brain which is responsible for neurological abnormalities in late stage of HIV infection and is one of the AIDS defining condition.

3. Role of lymphoid organ in HIV infection:

• Lymphoid organs play a central role in HIV infection.

• 98% of T-lymphocytes are resides in lymphoid organs

• They serves as reservoir of HIV

Role of CD4+ cells (T-lymphocytes, macrophages and monocytes) and lymphoid organs in HIV infection

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HIV Replication

• HIV uses CD4 molecule as a receptor which is present in CD4+ cells such as T-lymphocytes, macrophages, monocytes, dendritic cells other and Antigen presenting cells.

• A second co-receptor in addition to CD4 molecule is required for HIV to gain entry into host cell. CCR5 for macrophage tropic HIV and CXCR4 for T-lymphocyte tropic HIV.

• HIV first binds to CD4 molecule mediated by surface glycoprotein gp120 and then to the corresponding co-receptors CCR5 or CXCR4. This binding brings conformational change in viral envelope inducing the binding of gp41 of virus into host cell membrane and triggering the entry of virus into host cell.

• Once the fusion of virus takes place with the host cell, viral RNA is released into the cytoplasm.

• Viral RNA is then used to synthesize ds DNA by the enzyme reverse transcriptase (RNA dependent DNA polymerase). The ds DNA is then circularized and enter into host cell nucleus.

• This circular ds DNA get integrated with host genome and the process is catalyzed by the enzyme integrase. This type of integrated viral DNA into host DNA is known as Pro-virus.

• Once the viral DNA is integrated, infection of HIV is permanent.

• The HIV virus may then enter into latency or enter into productive cycle.

• In productive cycle, the pro-virus DNA is then transcribed into mRNA by host RNA polymerase and finally translated to viral proteins. These viral proteins are processed to form virion components which are then assembled.

• The progeny virus now mature and release by budding.

• During budding, it acquire envelope.

• The released progeny virus infects suitable host cell and continues the productive cycle.

Pathogenesis of HIV/AIDS

Pathogenesis of HIV can be described under following headings.

1. Mode of transmission:

HIV infection is acquired through one of the following routes.

• Sexual contact; infected partner
• Parental route; infected needles or syringes
• Congenital route; infected mother giving birth

2. Primary infection: (acute infection):

• Once HIV enters the body through any of those routes they bind to CD4+ cells with their glycoprotein spikes and infect the cell. Thus the infection is established.
• HIV multiply in mucosa and there is 4-11 days between mucosal infection and initial viremia. Viremia is detectable for about 8-12 weeks.

3. Dissemination of virion to lymphoid organs:

• Virus from blood is then disseminated throughout the body and seeded in lymphoid organs.
• In this stage, it leads to acute mononucleosis like syndrome
• The CD4 T- cells count drop significantly during this time.

4. Clinical latency:

• An immune response to HIV develops 1 week to 3 months after infection, which leads to significant drop in viral load and rebounce of CD4 T-cells.
• The immune response however is unable to clear the HIV completely.
• The HIV infected cells persists in lymph nodes leading to clinical latency.

5. Elevated HIV level:

• The period of clinical latency lasts as long as for 10 years.
• During latency virus replication continues. Consequently patients develop constitutional symptoms and clinical diseases such as opportunistic infections, neurological disorder and neoplasm.

6. Clinical disease and death:

• The duration between primary infection and progression to clinical disease is 10-12 years while death occurs usually within 2 years after unset of clinical disease ie. AIDS in untreated cases.

Clinical manifestation of HIV/AIDS

1. Acute retroviral syndrome (ARS):

• It can occurs few days to few weeks after primary infection.
• It is found in 50-70% of infected patients.
• It is characterized by clinical signs of immune activation and multi system dysfunction

Symptoms includes;

• acute mononucleosis like syndrome
• fever
• generalized lymphadenopathy
• sore throat
• fatigue
• weight loss
• rashes,
• nausea
• night sweat
• occasionally diarrhea
• pancreatitis
• bacterial sepsis
• epiglottitis
• self limiting neurological disorder,
• meningitis,
• encephalitis.

All these symptoms resolves within 5-30 days.

2. Clinical latency and incubation to AIDS

• ARS is followed by long period of clinical latency which is free of any clinical symptoms
• Clinical latency is maintained because of host immune response against HIV
• The median time to develop AIDS in untreated cases is 10-12 years.
• 5-10% of patients are rapid progressors and they develops AIDS within 2-3 years
• Similarly, 5-10 % other patients are non-progressors and they become free of symptoms after 7-8 years.
• In congenital infection clinical symptoms usually appears by 2 years of age and death occurs in next 2 years.

3. AIDS:

• Significant drops in CD4 T-cells count (below 200 cells/µl) leads to AIDS.
• AIDS results in loss of ability to respond to infections.
• Loss of immune response immune response develops opportunistic infection and tumors
• Other clinical symptoms are; Tuberculosis, Parasitic infection, Hepatitis, oral hairy leukoplankia, Kaposi sarcoma, Dementia complex and other neurological symptoms.

Lab diagnosis:

1. Serology: detection of anti-viral antibody using ELISA. This test detects serum antibody against gp120, gp41, P24 etc. The first positive result must be confirmed by at least 2 other different assays with different viral antigen.

2. Western blotting: It is a confirmatory test.

3. RT-PCR: detection of RNA and DNA sequence of HIV

4. Virus isolation: culturing on CD4 + T-lymphocyte cell line

HIV/AIDS: Replication, pathogenesis, clinical manifestation and lab diagnosis

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Structure and properties of HIV

1. Shape and size

• HIV is a spherical virus of about 90 nm in diameter.
• Size; 90nm

2. Envelope:

• HIV is enveloped virus. The envelope is a lipid bilayer surrounding the viral matrix, which is derived from host cell membrane during budding.
• Below the envelope, there is an icosahedral shell called matrix (P17).

3. Core:

• The core consists of cylindrical capsid (P24) which surrounds the genome.

4. Genome:

• HIV is ss RNA virus. The genome consists of two identical copies of +SS RNA and protein which are linked at their 5’ end.
• Genome of HIV consists of 9 gene, 3 structural gene and 6 non-structural gene (regulatory gene).
• Structural gene (env,gag and pol), regulatory gene (tat,rev,nef,vif,vpr and vpu in HIV-I and vpx in HIV-2)

5. Enzymes:

• Reverse transcriptase (RNA dependent DNA polymerase)
• Protease
• Intrigase
• Ligase

6. Replication:

• Cell specific (CD+T cell)
• Virus entry: receptor mediated (gp120 and gp41)
• RNA Replicates to form DNA intermediate by Reverse transcriptase enzyme
• Provirus remains permanently associated with host cell
• Release; budding

7. Other properties:

• Oncogenic
• Mutation
• Species specific
• Family: Retroviridae

HIV genome and proteins

• HIV has two identical copies of +SS RNA genome. The genome consists of 3 structural gene and 6 regulatory gene.
• Structural gene; env, gag and pol gene
• Regulatory gene; tat, rev, nef, vif, vpr and vpu in HIV-I and vpx in HIV-2)

1. Structural gene:

i. Gag gene:

• Gag gene encodes the precursor protein P55 which is cleaved by viral protease (P10) to form matrix protein (P17), Capsid protein (P24) and Nuncleocapsod protein (P7 & P9). Gag gene helps to form core of virus.

ii. Pol gene:

• Pol gene encodes the precursor protein P100 which is cleaved to form Protease (P10), reverse transcriptase and endonuclease.

iii. Env gene:

• Env gene encodes the precursor protein gp160 which is cleaved to form surface spike glycoprotein (gp120) and transmembrane protein (gp41).
• Genetic variety of HIV strain resides in env

2. Regulatory gene:

i. Tat gene: ( transactivator of transcription)

• It encodes transactivator protein (P14) which promotes the transcription of viral genome.

ii. Rev gene: (regulatory of expression of viral protein)

• It encodes Rev protein (P19) and promotes the expression of viral structural proteins

iii. Nef gene: ( Negative expression factors)

• It encodes precursors protein P27
• It down regulates the expression of CD4 cells, macrophage and MHC-II.

iv. Vif gene: (Virion infectivity factor)

• It encodes the precursor protein p23 and promotes the viral infectivity by suppression the inhibitory actions of host cell proteins.

v. Vpr gene:

• It encodes the precursor protein P15.
• It promotes the transport of viral pre-initiation complex into nucleus of host cell.

vi. Vpu gene in HIV-I / Vpx gene in HIV-II

• It encodes the precursor protein P16.
• It promotes maturity and releases of progeny virus from host cell.

Structure, genome and proteins of HIV

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