HIV--AIDS

Immunodeficiency

Is an absent or inadequate response of the immune system usually resulting in increased susceptibility to other diseases or opportunistic infection

Cells and mediators involved in HIV

• B cells

• T cells

• Complement, or phagocytes

• Cell-mediated and/or humoral responses are affected

Acquired immunoincompetence often results from?

• Bacterial or viral infection

• Malnutrition, or exposure to radiation or certain drugs

Viruses

They are pieces of DNA or RNA in a protein shell. Viruses may be enveloped or naked

How are virus obligate intracellular parasites?

• A virus must enter a cell to reproduce

• Virus directs infected cells to make copies of nucleic acid and capsid (protection for viral genome)

• The virus or immune response may kill the host cell

Acquired immunodeficiency syndrome (AIDS) is caused by?

The human immunodeficiency virus (HIV)

HIV emergence and evolution is fairly recent (1981)

Originally was associated with homosexual males based on high case counts of AIDS reported by clinicians in New York, San Francisco, and Los Angeles

HIV is transmitted through?

• Blood

• Semen

• Vaginal fluids

• Breast milk

Estimation of HIV-infected people in the US

1.2 million people in the US, Doesn’t necessarily mean they have symptoms or AIDS

Estimation of HIV infected people globally

39.9 million people globally, Doesn’t necessarily mean they have symptoms or AIDS

People with HIV infection are infectious even when?

Asymptomatic

HIV Classification

Retroviridae family, lentivirus subfamily

Subtypes of hIV

• HIV1(global outbreaks=HIV1)

• HIV2 (West Africa)

What cell does HIV targets?

• CD4+ T lymphocytes (T-helper cells)

• Macrophages

• Dendritic cells

T helper cells

They are mediators of immune responses, coordinating humoral (activate antibody-producing B cells) and cellular immunity (activate cytotoxic T cells and NK cells)

CNS (Trojan horse)

“microglial cells and macrophages support HIV infection in the brain dynamically, while infection of neurons and oligodendrocytes is seldom. The HIV infection to astrocytes causing astrocytosis is also well reported.”

HIV virus are enveloped by?

Glycoproteins (GP) 120 and 41

GP 120 and GP 41

They are required for attachment and entry into the host

What does GP 120 do?

Binds to CD4 (T helper cells)

What does GP 41 do?

Binds to co-receptors (CCR5, CXCR4). Chemokine coreceptors 5 (CCR5) and 4 (CXCR4)

Viral core of HIV

• p24(major capsid protein)

• Two copies of genomic RNA

• 3 viral enzymes

Viral enzymes includes?

• Reverse transcriptase (RT)

• Integrase

• Protease

HIV mechanism of action

1. Attachment

2. Fusion and Uncoating

3. DNA synthesis

4. Integration

5. Transcription

6. Translation

7. Cleavage

8. Assemble and Release

Step 1 of HIV mechanism: Attachment

Virus binds to T helper cell using envelope proteins gp120 and gp41 then through binding to chemokine coreceptors 5 (CCR5) and 4 (CXCR4)

Step 2 of HIV mechanism: Fusion and Uncoating

The viral envelope fuses to the T cell membrane and the virus releases RNA and enzymes into the T cell’s cytoplasm

Step 3 of HIV mechanism: DNA synthesis

RNA is reverse-transcribed to dsDNA using RT enzyme

Step 4 of HIV mechanism: Integration

Viral dsDNA enters the nucleus and inserts into host cell DNA using integrase enzyme (results in the formation of a provirus)

Step 5 of HIV mechanism: Transcription

Host cell machinery will transcribe viral DNA to mRNA

Step 6 of HIV mechanism: Translation

mRNA and rRNA are templates for the host ribosome to make a viral polyprotein (chain of proteins and enzymes)

Step 7 of HIV mechanism: Cleavage

Protease enzyme cuts polyprotein chain into individual proteins

Step 8 of HIV mechanism: Assemble and Release

New viruses are assembled from replicated RNA and proteins and then bud from the cell

Phases of HIV infection

• Primary infection (active phase)

• Latent period (chronic asymptomatic phase)

Primary infection (active phase)

• Lasts for a few weeks

• Acute mononucleosis-like syndrome symptoms: lymphadenopathy (swollen lymph nodes), weight loss, fatigue, diarrhea, and night sweats

• Viral replication and load are high

Latent period (chronic asymptomatic phase)

• Can remain in this phase for 10 years (median)

• No signs or symptoms

• Low viral loads but still risk to infect others

• T helper cell counts decline (200 cells/uL – 1000 cells/uL)

• Group of immune cells infected with HIV but not actively producing new HIV thus the resting state of infection

Reservoir

It is a replication-competent form of a virus that accumulates and persists. Some cells of HIV reservoir are memory CD4 T cells

Other cells acting as reservoirs of HIV include?

• Macrophages: are not killed by viral cytopathic actions

• Dendritic cells: acting as APCs present viral fragments to T cells infecting T cells

Overt AIDS:

• Prognosis = 2-3 years

• Very low T helper cell counts (less than 200 cells/uL)

Death of uninfected CD4+ T cells in lymph nodes

• Bystander” T cells die due to apoptosis

• Stimuli that trigger apoptosis: overexpression of death ligands (tumor necrosis factor-α, Fas ligand, and TRAIL) on infected immune cells or direct cytotoxicity of HIV proteins (gp120) and even exosome activity

Direct virus attack leading to cytolytic effects

• CD4 T cell infection is counteracted by T cell production

• Balance is disrupted once T cell production is exhausted

• Infection continues to spread attacking memory cells in the thymus viral replication within the thymus

• Infected memory CD4 cells in the thymus are eliminated contributing to a progressive decline of CD4 cells

HIV-associated immune activation is characterized by?

High levels of proinflammatory cytokines and chemokines

Cytokines contribute to?

Immune activation of more cells which leads to more targets causing greater cell death and loss of immune cells to fight infection

Link between events of HIV infection

• CD4 T cell depletion and chronic inflammation.

• Dying cell releases cytoplasmic contents and inflammatory cytokines

• Cytokines trigger pyroptosis in other T cells

Pyroptosis

High inflammatory form of apoptosis

Kaposi sarcoma

Is an aggressive malignancy of the blood vessels that appears as purple or blue patches on the skin, in the mouth, or anywhere else on the body.

Lymphomas

Are cancerous lesions of lymphoid tissues.

Pneumocystis carinii pneumonia (PCP)

It is a lung infection that can progress to be life-threatening. It is the most common lung disease in persons with AIDS.

Tuberculosis

Is a bacterial infection of the lungs or other organs.

Herpes simplex infection

Consists of painful blister-like lesions of the mouth, genitalia, or anus caused by the herpes virus.

Herpes zoster (shingles)

Is characterized by clusters of red, blister-like skin lesions that are distributed along the distribution of an inflamed nerve.

Candida albicans

Causes a fungal infection of the mucous membranes of the mouth, genitalia, or skin.

Toxoplasmosis

Is an infection caused by a protozoan intracellular parasite. A rash and lymphadenopathy can be present, and the central nervous system (CNS), heart, or lungs can become involved.

Neurologic complications

include inflammation of nerves, neuropathy, neoplasms, and AIDS dementia complex.

Diarrhea

Is a symptom of a host of bacterial and viral infections of the gastrointestinal (GI) tract, liver, or gallbladder.

Epstein-Barr virus

Causes hairy leukoplakia that is characterized by white plaque visible on the tongue.

Treatment of HIV

HAART (Highly Active Antiretroviral Therapy)

• protease inhibitors

• reverse transcriptase inhibitors

• integrase inhibitors

• chemokine receptor antagonists

• fusion inhibitors

Prevention and prognosis of HIV

• Although AIDS is ultimately a fatal disease, the number of Americans dying of AIDS each year has dropped. Treatment strategies that result in better prognosis include the use of HAART, the use of prophylactic antibiotics, and care by a physician experienced in HIV care.

• The use of HAART significantly decreases the risk of HIV transmission to an HIV-seronegative sexual partner.

• Use of condoms and not sharing needles are highly recommended.

• The drugs used in HAART can be administered as postexposure prophylaxis after a needlestick injury.

• Patients who test positive for HIV infection should be encouraged to inform their sexual partners because they may be at high risk for contracting the disease.

Reverse Transcriptase Inhibitors (NRTIs)

• NRTIs require intracellular phosphorylation via host enzymes before they can inhibit viral
  replication.

• These agents are nucleoside or nucleotide analogs with an absent hydroxyl at the 3’ end that are incorporated into the growing viral DNA strand.

• They competitively
  bind to reverse transcriptase and cause premature DNA chain termination as they inhibit 3’ to 5’ phosphodiester bond formation.

Protease inhibitors (PIs)

PIs competitively inhibit the proteolytic cleavage of the gag/pol polyproteins in HIV-
infected cells. These agents result in immature, non-infectious virions.

Integrase Inhibitors (INSTIs)

Integrase inhibitors bind viral integrase and prevent viral DNA from being incorporated
into the host cell chromosomes

Fusion inhibitors (FIs)

Fusion inhibitors bind to the envelope glycoprotein gp41 and prevent viral fusion to the
CD4 T-cells.

Chemokine Receptor Antagonists (CCR5 Antagonists)

CCR5 antagonists selectively and reversibly block entry into the CD4 T-cells by
preventing interaction between CD4 cells and the gp120 subunit of the viral envelope
glycoprotein.