HIV Infection: Epidemiology, Diagnosis, Transmission, and Immune Response - Prof. Phalguni, Study notes of Biology

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HIV Pathogenesis

Viral Pathogenesis Course

Instructor: Phalguni GuptaInstructor: Phalguni Gupta

Epidemiologic Facts of

HIV in World

Global: 40-60 million with HIV infection 33.4 million developed AIDS

Africa: Population 680 million 25 million HIV infected25 million HIV infected 10 million AIDS

US: Population 200 million 1 million HIV infected

India: Population 1.0 Billion China: Population: >1.2 billion 4.0 million HIV infected 1.2 million HIV-infected 0.16-0.36 million AIDS 0.05 million AIDS WHO report, 2004

HIV heterogeneity

• HIV is not a single virus. It is a highly

heterogeneous virus.

• Genetic sequence analysis of HIV around the

world indicates 3 majorj ggroups: p

– M ( Major), N (New) and O (outlier)

– M is comprised of clades/subtypes A‐J.

• At genetic level HIV could be as much as 20 ‐

40% different between two patients and 5 ‐

15% within the same patient.

Diagnosis of HIV Infection

Indirect Methods:

• serologic assays a) ELISA b) Western blot c) Immunofluorescent assays d) Radioimmunoprecipitation
• latex agglutination assay

Direct Methods:

• virus culture
• p24 antigen capture assay
• detection of HIV DNA by PCR
• detection of HIV RNA by a) RT PCR b) branched DNA (bDNA) assay c) Nucleic Acid Sequence Based Amplification (NASBA)

Major Modes of HIV Transmission

1. Sexual
   • Homosexual
   • Heterosexual
2. Blood and Blood Products
   • Transfusion
   • Blood clotting factors
   • Intravenous drug usage
   • Exposure to blood in health care setting
3. Transmission from Mother to Child3. Transmission from Mother to Child
   • Prenatal
   • Perinatal (during delivery)
   • Breast feeding

How HIV is Not Transmitted

1. Casual contact
2. Biting or kissing
3. Mosquitoes for flies

HIV-

Source: NIAID

CD

CCR5 or CXCR

Endoscopic and histological analysis of GI tract of a person with acute HIV-1 infection

CD4 T cells are stained in histologic sections

Douek, et al., 2004

% CD4 T cells in uninfected and HIV- infected persons

Douek, et al., 2004

HIV Attachment and

Fusion Targets for Inhibition

Virus-Cell

Fusion

CD

Binding

Co-receptor

Binding

gp gp V3 loop CD

Cell Membrane CCR5/CXCR (R5/X4) Adapted from Moore JP et al****. PNAS 2003;100:10598-10602.

• HIV‐ 1 uses β‐ Chemokines as co‐receptors, CCR5 and CXCR

Summary of HIV co‐receptors

CXCR

• Different strains of HIV‐ 1 use different co‐receptors.
• Different cells have different Co‐receptors.
  • Primary CD4+ T cells carry both CCR5 and CXCR
  • Transformed T cell lines carry mainly CXCR
  • Primary macrophages carry CCR
• Envelop V3 region is important for co‐receptor recognition.

Immune Control of HIV Infection

Role of antibody

Antibodies are not able to control HIV infection

• Antibodies in infected subjects have a weak neutralizing antibody
• Extensive gg ylycosylation of y env proteinp makes renders virus ppoorly y accessible to neutralizing antibody
• Neutralizing antibody develops after initial burst of viral replication
• Depletion of B lymphocytes in monkeys delayed emergence of neut. Ab, but did not have any effect on viral clearance

During both the acute and chronic phases of HIV

infection, production of cytotoxic T lymphocytes

(CTLs) by the host immune system exerts a strong

HIV escape from CTL control

(CTLs) by the host immune system exerts a strong

inhibitory effect on HIV growth and replication.

Therefore, it is not surprising that there is strong

selective pressure for survival of HIV mutants that

escape the CTL response

McMichael and Klenerman, Science 2002

Hallmark of AIDS Development

• Decrease in CD4 cell number

• Increase in viral load

• Transition of less virulent R5 virus to more

virulent X4 virus

• Increase in viral diversity

Rapid Progressors

V-1 Viral Load

Divergent Disease Progressions in HIV-1 infection

8 – 12 weeks 8-10 years

Long Term Non-Progressors

HIV

years

Characteristics of long term non‐progressor

• Stable CD4 cell number for more than 7 years
• Clinically asymptomatic
• Low viral load
• High memory CTL activity
• R5 tropic virus

Makedonas, et al., 2005

Scatter plot of HIV-specific responses in seronegative subjects exposed to HIV mucosally (Group I) and parenterally (Group II).

HIV early infection and T cell events: High risk seronegatives (HRSNs) or exposed uninfecteds [EUs])

• About 5% of high‐risk persons appear resistant to

mucosal infection with HIV‐1; others are resistant to

blood‐borne infection (e.g., via needle sticks).

• 1% of population is resistant to HIV‐ 1 due to

CCR5neg^ /CCR5neg^ mutation; rare infection now reported;

only accounts for small % of HRSNs.

• Not known why others are resistant to HIV‐ 1 infection, as

virus can replicate in their T cells and macrophages in

vitro.

• Resistance due to CTL? CD8+^ cell antiviral factor (CAF)?

CD4+^ T cell reactivity? Other forms of immunity?

Mechanisms of CD4+ T Cell Dysfunction and Depletion

Direct mechanisms

• Accumulation of unintegrated viral DNA
• Interference with cellular RNA processing by high level of viral RNA
• Intracellular gp120‐CD4 autofusion leading to disruption of cell membrane and cell death
• Uncontrolled replication leading to lysis of cells

Problem: Frequency of HIV‐infected cells is mostly 0.1%. Therefore, direct mechanism cannot explain vast depletion of CD4 over time.

A ti HIV 1 CTL

HIV

VIRUS

HIV-1 HAART

OFF HAART HAART + Immunotherapy Off treatment

Effects of HAART on anti-HIV-1 T cell responses in chronic infection: Can immunotherapy help control residual HIV-1?

Years

Anti-HIV-1 CTL

Anti-HIV- CD4 +^ TH1 cells

Piazza, Fan and Rinaldo, 2002

Viral reservoir after therapy