ImmunoPathogenesis of HIV Disease

• Overview of HIV Epidemic• Basic biology of HIV-1• Stages of HIV Disease • Viral and Cellular Dynamics after HAART• HIV Therapy and Future Directions in

Pathogenesis Research

Overview of HIV Epidemic• Origin of virus• Scope of worldwide Epidemic• Brief History of Epidemic

– Immunodeficiency syndrome identified (GRID) in late 1970’s – Identification of virus and development of serological test - 1984 – Introduction of first antiretroviral drug (AZT) – 1987– Identification of three stages of disease – early 1990’s – Competitive RT-PCR to measure viral RNA in plasma – 1993 – combination antiretroviral drugs (protease inhibitors & RTI) – 1995 – Introduction of ART to Africa – 2001– Epidemic still expanding – 2006

Death rates in persons aged 25-44 years in the United States

A global view of HIV infection38.6 million people [33.4‒46.0 million] living with HIV, 2005

Life cycle of HIV

• Viral Entry - CD4 and co-receptors• Reverse Transcription• Integration into host chromatin• Transcriptional activation of integrated provirus• Production of viral proteins, particle assembly

and maturation

Chemokine Co-receptors for HIV• Two co-receptors - CXCR4 and CCR5 with distinct viral

isolates • CXCR4 - T tropic - syncytium inducing - present in late

stage disease• CCR5 - M tropic - non- syncytium inducing - dominant

in early infection• Natural ligands - SDF-1/CXCR4 & MIP-1a, MIP-1b, &

RANTES/CCR5• Protection from infection in CCR5 D32 homozygotes

HIV Latent Infection • Pre-integration latency

– After reverse transcription, before integration– Due to lability of unintegrated DNA, this pool is dependent on

continual de novo infection

• Integrated latency– Integrated provirus with low or absent transcription of viral

genes (no expression ® no clearance)– Likely the major reason for eradication failure– Controversy about origin, role of defective viral genomes,

chromatin integration sites, and clearance rate

High viral mutation rate• Reverse Transcriptase is fairly sloppy and cellular RNA

polymerases are not high fidelity enzymes

• Estimated to be around 1000 different sequence variants in a single individual at one time

• Rapid evolution of drug resistance, if there is continued de novo infection

• In general, inverse relationship of “viral fitness” in vivo growth rate and drug resistant phenotype. Wild type virus grows out when drugs withdrawn.

• Partial drug mediated inhibition of growth is recipe for resistance

Diagnosis of HIV Infection

• Signs & Symptoms of Primary Infection • HIV Ab measurement (EIA Western Blot)• HIV viral RNA in plasma• Response to suspected exposure (needle stick)• Post-exposure prophylactic ART

Laboratory Testing for AIDS• Antibody testing —to diagnose HIV infection.

• p24 protein testing —may be used to detect early HIV infection, to monitor HIV therapy and HIV progression, and to screen blood for HIV.

• Viral load testing —to decide when to start therapy and to monitor therapy and HIV progression. – In chronic phase, the extent of viremia (as measured by HIV-1 RNA) can predict

disease progression

• CD4 testing —to decide when to start therapy and to monitor therapy, HIV progression, and the status of the immune system. – >500 asymptomatic– 200-499 early symptoms– <200 severe immunosuppression

• Genotypic resistance testing —to determine if a particular strain of HIV is resistant to the therapy you are on and if the therapy should be switched.

Occupational Exposure to HIV

• Concept of Universal precautions – Any human bodily fluids could be contaminated with

infectious agents transmitted by parenteral exposure.

• In case of possible exposure, immedately report to HIV response team (at UAB 4-3675) or ER.

• Early Treatment with antiretroviral drugs have very substantial benefit– Time after infection is critical. – Excellent results if ART started within several days.

Three Phases of HIV Disease

• Acute Infection Syndrome– “flu-like” clinical illness– high viral load that resolves coincident with development of

effective CD8 T cell response

• Clinical “Latent” Disease– Widely variable viral load correlated with rate of disease

progression (loss of CD4 T cells)– Lymphadenopathy and constitutional symptoms

• End Stage Disease (AIDS) – CD4 T cells < 200; often increase in viral load– development of opportunistic infections

InfectionsPROTOZOAL AND HELMINTHIC INFECTIONS

  Cryptosporidiosis or isosporidiosis (enteritis)  Pneumocystosis (pneumonia or disseminated infection)  Toxoplasmosis (pneumonia or CNS infection)

  Candidiasis (esophageal, tracheal, or pulmonary)  Cryptococcosis (CNS infection)  Coccidioidomycosis (disseminated)  Histoplasmosis (disseminated)

Mycobacteriosis ("atypical," e.g., Mycobacterium avium-intracellulare, disseminated or extrapulmonary; M. tuberculosis, pulmonary or extrapulmonary)Nocardiosis (pneumonia, meningitis, disseminated)Salmonella infections, disseminated

VIRAL INFECTIONS  Cytogegalovirus (pulmonary, intestinal, retinitis, or CNS infections)  Herpes simplex virus (localized or disseminated)  Varicella-zoster virus (localized or disseminated)  Progressive multifocal leukoencephalopathy

  Kaposi sacroma  Non-Hodgkin lymphomas (Burkitt, immunoblastic)  Primary lymphoma of brain  Invasive cancer of uterine cervix

AIDS-Defining Opportunistic Infections and Neoplasms in HIV Infection

FUNGAL INFECTIONS

BACTERIAL INFECTIONS

Neoplasms

Time

Log

Pla

sma

vRN

A

1

2

3

4

5

6

7

8

Initial RateIndependent of Absolute vRNA

t½ 1 day

HAART

Viral Dynamics after HAART

Dynamics of HAART Induction• Rapid fall in viral RNA in plasma

– First phase is very rapid (t½ = 1-1.5 days) and fairly consistent among individuals, second phase slower.

• Rapid Increase in CD4 T cells in Blood– Redistribution of lymphocytes from inflammed tissue is

primary mechanism - previously thought to be change in CD4 T cell growth

• Significant Immune Reconstitution – Decreased incidence of OIs and death

• Despite initial optimism, infection not eradicated

• Concept of Reservoir - residual viable virus during HAART– Latently infected CD4 T cells– Sequestered Anatomic site - CNS, ?others– Persistent rounds of de novo infection– Intermittent Non-adherence

• Slow evolution of viral quasispecies sequences

Status of HIV Dynamics on HAART

Both Latent infection and persistent vRNA+ cells - Tissue and Blood

Goals in Medical Management of HIV Disease

• Pharmacological suppression of viral Replication– Multiple drugs available – low replication low mutations– Monitoring status – viral load and CD4 count

• Eradication - complete elimination of viable virus – Problems - HAART alone does not result in Eradication.

Regimen is difficult - Intermittent regimen Non-Adherence Development of Drug Resistance Persistent population of latently infected CD4 T cells

• Induction of Immune Control– Increase efficiency of immune response to viral antigen to

maintain control of replication at very low viral load – Low viral load = Lack of disease progression– Normal “successful” outcome of chronic viral infection