Human Immunodeficiency Virus & AIDS 2 Classification of

Human Immunodeficiency Virus & AIDS 2 Classification of

Human Immunodeficiency Virus & AIDS 2 Classification of HIV HIV class: Lentivirus Retrovirus: single stranded RNA transcribed to double stranded DNA by reverse transcriptase Integrates into host genome High potential for genetic diversity Can lie dormant within a cell for many years,

especially in resting (memory) CD4+ T4 lymphocytes HIV type (distinguished genetically) HIV-1 - worldwide pandemic (current ~ 40 M people) HIV-2 - isolated in West Africa; causes AIDS much more slowly than HIV-1 but otherwise clinically similar 3 Classification of HIV-1 HIV-1 Groups

M (major): cause of current worldwide epidemic O (outlier) and N (Cameroon): rare HIV-1 groups that arose separately HIV-1 M Subgroups (Clades) >10 identified (named with letters A to K) Descended from common HIV ancestor One clade tends to dominate in a geographic region

Clades differ from each other genetically Different clades have different clinical and 4 biologic behavior Origin and Distribution of HIV-1 Clades HIV-1 rapidly evolves by two mechanisms: Mutation: changes in single nucleosides of the RNA Recombination: combinations of RNA sequences from two distinct HIV strains Several common clades (e.g., A/G ad A/E) are recombinants Geographic

5 distribution of HIV group M clades A in Central Africa B in North American, Australia, and Europe C in Southern and Eastern Africa (Ethiopia) 6 HIV Entry into Cells gp120 env protein binds to CD4 molecule

CD4 found on T-cells macrophages, and microglial cells Binding to CD4 is not sufficient for entry V3 loop of gp120 env protein binds to co-receptor CCR5 receptor - used by macrophage-tropic HIV variants CXCR4 receptor - used by lymphocyte-tropic HIV variants Binding of virus to cell surface results in fusion of viral envelope with cell membrane

Viral core is released into cell cytoplasm 7 Viral-host Dynamics About 1010 virions are produced daily life-span of an HIV virion in plasma is ~6 hours

Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses 8 General Principles of Viral-host Interactions Host: mounts HIV-specific immune responses Cellular (cell-mediated) - most important

Humoral (antibody-mediated) Virus: subverts the immune system Infects CD4 cells that control normal immune responses Integrates into host DNA High rate of mutation Hides in tissue not readily accessible to immune system Induces a cytokine environment that the virus uses to its own replicative advantage 9 Achieved by activation of the immune system

HIV Evasion Methods Makes 10 billion copies/day with rapid mutation of HIV antigens Integrates into host DNA Depletes CD4 lymphocytes Down-regulation of MHC-I process Impairs Th1 response of CD4 helper T lymphocyte Infects cells in regions of the body where antibodies penetrate poorly, e.g., the central nervous system 10 Cells Infected by HIV

Numerous HIV: organ systems are infected by Brain: macrophages and glial cells Lymph nodes and thymus: lymphocytes and dendritic cells Blood, semen, vaginal fluids: macrophages Bone marrow: lymphocytes Skin: langerhans cells Colon, duodenum, rectum: chromaffin cells Lung: alveolar macrophages 11

General Mechanisms of HIV Pathogenesis Direct injury Nervous (encephalopathy and peripheral neuropathy) Kidney (HIVAN = HIV-associated nephropathy) Cardiac (HIV cardiomyopathy) Endocrine (hypogonadism in both sexes) GI tract (dysmotility and malabsorption) Indirect injury

Opportunistic infections and tumors as a consequence of Immunosuppression 12 General Principles of Immune Dysfunction in HIV All elements of immune system are affected Advanced stages of HIV are associated with substantial disruption of lymphoid tissue Impaired ability to mount immune response to new antigen Impaired ability to maintain memory

responses Loss of containment of HIV replication Susceptibility to opportunistic infections 13 Mechanisms of CD4 Depletion and Dysfunction Direct Elimination of HIV-infected cells by virusspecific immune responses Loss of plasma membrane integrity because of viral budding Interference with cellular RNA processing Indirect Syncytium formation

Apoptosis Autoimmunity 14 Pathogenesis Major targets of HIV-1 are the lymphoreticular, hematopoietic, and nervous systems. Critical target cells are dendritic cells, CD4+ cells and monocyte -macrophages.

Macrophage-tropic Vs T-lymphocyte-tropic isolates. During primary infection, high levels of plasma and cell associated viremia occur. Almost all viruses present in an individuals circulation are the product of recently infected cells. Early Phase HIV Infection

In early phase HIV infection, initial viruses are Macrophage-tropic. Their envelope glycoprotein gp120 is able to bind to CD4 molecules and chemokine receptors called CCR5 found on macrophages Late Phase HIV Infection In

late phase HIV infection, most of the viruses are T lymphocyte -tropic, having gp120 capable of binding to CD4 and CXCR4 found on T4lymphocytes. Virus is readily detectable in peripheral blood and lymph nodes throughout the course of infection. Fatal

disease occurs because the virus outpaces the immune system and causes progressive depletion of CD4+ T cells Disease progression appears related to degeneration of the follicular dendritic network and loss of the HIV-trapping capacity. Virus load at any point of time is an important determinant.

The best quantitative indicator of future disease is the level of virus that persists in the blood plasma once the symptoms of acute viremia have passed. Before the availability of effective treatment, over 95% of HIV infected individuals used to progress to AIDS within 15 years of infection. AIDS

is a constellation of clinical illnesses, primarily opportunistic infections and malignancies. Manifestations can be attributed to the loss of the functions of the CD4+ T lymphocytes. The CD4+ T cell count in peripheral blood is used as the most important basis for staging of the disease.

Mothers who are newly infected and breast feed their infants transmit HIV 40% of the time, showing that HIV can also be transmitted in breast milk. Between 15% and 30% of children born to untreated HIV-infected mothers acquire infection. Recent

studies have shown that this rate can be reduced to ~5% when HIV infected pregnant women receive antiviral drugs. Clinical Features Acute primary Infection Syndrome [clinical category A (CD4 T Cells >500)] Asymptomatic Infection and Persistent Generalized Lymphadenopathy (PGL/ clinical category A)

Symptomatic HIV Infection (clinical categories B [CD4 T Cells 200-499) and C (CD4 T Cells <200)] - Primary HIV Syndrome Mononucleosis-like, cold or flu-like symptoms may occur 6 to 12 weeks after infection. Lymphadenopathy

fever rash headache Fatigue diarrhea sore throat neurologic manifestations. no symptoms may be present Primary HIV Syndrome Symptoms are relatively nonspecific.

HIV antibody often tests negative but seroconversion takes place within 3 to 6 months. High counts of HIV are present in the peripheral blood Primary HIV syndrome can be diagnosed using viral load titer assay or other tests. Primary HIV syndrome resolves itself and an HIV

infected person remains asymptomatic for a prolonged period of time, often years. typical primary HIV-1 infection symptoms symptoms HIV proviral DNA HIV antibodies window period HIV viral load HIV-1 p24 antigen

0 1 2 1 infection 3 4 5 6

/ 2 4 6 weeks Time following infection 8 years 10

Clinical Latency Period HIV continues to reproduce, CD4 count gradually declines from its normal value of 500-1200. Once CD4 count drops below 500, HIV infected person is at risk for opportunistic infections. The following diseases are predictive of the

progression to AIDS: persistent herpes-zoster infection (shingles) oral candidiasis (thrush) oral hairy leukoplakia Kaposis sarcoma (KS) Oral Candidiasis (thrush) Oral Hairy Leukoplakia Being that HIV reduces immunologic activity, the intraoral environment is a prime target for chronic secondary infections and inflammatory processes, including OHL, which is due to the

Epstein-Barr virus under immunosuppressed conditions Kaposis sarcoma (KS) Kaposis sarcoma is a rare cancer of the blood vessels that is associated with HIV. It manifests as bluish-red ovalshaped patches that may eventually become thickened. Lesions may appear singly or in clusters.

AIDS When CD4 count drops below 200 the person is considered to have advanced HIV disease If preventive medications are not started, the HIV infected person is now at risk of: Pneumocystis carinii pneumonia (PCP) Cryptococcus meningitis Toxoplasmosis

If CD4 count drops below 50: Mycobacterium avium intracellulare complex Cytomegalovirus infections lymphoma dementia Most deaths occur with CD4 counts below 50. AIDS-Related Diseases Central/peripheral Nervous system Cytomegolavirus Toxoplasmosis Cryptococcosis Non Hodgkin's

lymphoma Varicella Zoster Herpes simplex Respiratory system Pneumocystis Carinii Pneumonia (PCP) Tuberculosis (TB) Kaposi's Sarcoma (KS) Gastro-intestinal system

Cryptosporidiosis Candida Cytomegolavirus Skin (CMV) Herpes simple Isosporiasis Kaposi's sarcoma Kaposi's Sarcoma Varicella Zoster Infants with HIV Failure

to thrive Persistent oral candidiasis Hepatosplenomegaly Lymphadenopathy Recurrent diarrhea Recurrent bacterial infections Abnormal neurologic findings. HIV encephalopathy (AIDS dementia complex)

Dementia - persistent cognitive decline with preserved alertness Complex - concomitantly altered motor performance and, at times, behavior; myelopathy may be prominent Disabling condition that interferes with activities of daily living Progresses over weeks to months Absence of concurrent illness or condition that could explain findings Limited treatment options; ART may be helpful 33 HIV wasting syndrome

Weight loss >10% body weight plus Unexplained chronic diarrhea (>1 mo) or Unexplained fever (>1 mo) plus chronic weakness 34 Kaposis sarcoma Epidemiology

Human herpesvirus-8 (HHV-8) necessary but not sufficient for KS to develop most common AIDS-associated neoplasm increased frequency in all HIV transmission groups compared to the general population Clinical manifestations Variable, from an indolent process to a disseminated, aggressive disease skin lesions oral lesions 35 others sites Kaposis Sarcoma 36

Courtesy of Tom Thacher, MD Laboratory to AIDS Markers of Progression - Increased viral load - P24 antigenemia - Decline of anti P24 antibodies - CD4+ T cell count below 200 cells/mm3 WHO guidelines for clinical diagnosis of AIDS in adults

2 major signs & 1 minor sign (in absence of other explanation) Major signs: 1. Weight loss > 10% bodyweight 2. Diarrhea > 1 month 3. Fever > 1 month 38 WHO guidelines for clinical diagnosis of AIDS in an adult Minor signs: 1. Widespread enlarged lymph glands 2. Persistent cough for more than 1 month 3. Thrush (candida) of mouth & throat

4. Widespread itchy skin rash 5. Recurring shingles (herpes zoster) 6. Chronic, severe, spreading cold sores (HSV1) 7. Loss of memory 8. Loss of intellectual capacity 9. Peripheral nerve damage 39 WHO Staging System for HIV/AIDS: Overview Tool used to guide management of HIV patient in resource limited settings with limited laboratory access

Clinically based; CD4 count not required Simple, flexible and widely used Recently revised: Interim African version 2005 Utilizes 5 clinical stages based on the degree of immunocompromise and prognosis 40 Primary HIV Infection, I,II, III, IV WHO Staging System for HIV/AIDS: Overview (2) Performed at each clinical visit Diagnosis Entry to clinical care (pre-ART)

Follow-up Stage assessment can be adjusted upwards or downwards over time according to response to ART and/or clinical progression 41 WHO Staging of HIV/AIDS Primary HIV Infection Stage I - asymptomatic Stage II - mild disease Stage III - moderate disease

Stage IV - advanced immunocompromise 42 WHO Stage I Asymptomatic or Persistent generalized lymphadenopathy (PGL) 43 44 Persistent Generalized

Lymphadenopathy (PGL) WHO Stage II Moderate unexplained weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections (RTIs, sinusitis, bronchitis, otitis media, pharyngitis)

Herpes zoster Angular cheilitis Recurrent oral ulcerations Pruritic papular eruptions Seborrhoeic dermatitis Fungal nail infections of fingers 45 Pruritic Papular Eruption 46 Courtesy of Charles Steinberg MD Pruritic Papular Eruption

47 Courtesy of Charles Steinberg MD Apthous Ulcer 48 Source: Copyright 1996-2000 David Reznik, D.D.S. Herpes Zoster Courtesy of Tom Thacher, MD 49 Courtesy of the Public Health Image Library/CDC

Herpes Zoster 50 Courtesy of Samuel Anderson, MD Molluscum Contagiosum 51 WHO Stage III Conditions where a presumptive diagnosis can be

made on the basis of clinical signs or simple investigations Severe weight loss (>10% of presumed or measured body weight) Unexplained chronic diarrhea for > one month Unexplained persistent fever (intermittent or constant for > one month) Oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis (TB) diagnosed in last two years Severe presumed bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteremia) Acute necrotizing ulcerative stomatitis, gingivitis 52 or periodontitis

WHO Stage III (2) Conditions where confirmatory diagnostic testing is necessary Unexplained anemia (<8 g/dl), and or Neutropenia (<500/mm3) and or thrombocytopenia (<50 000/ mm3) for more than one month 53 Oral Candidiasis Courtesy of Samuel Anderson, MD

54 Courtesy of Dr. R. Ojoh Oral Candidiasis (2) 55 Source: Oral Hairy leukoplakia Courtesy of Dr. R. Ojo 56

Pyomyositis 57 Courtesy of Samuel Anderson, MD WHO Stage IV Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations HIV wasting syndrome Pneumocystis pneumonia Recurrent severe or radiological bacterial pneumonia

Chronic herpes simplex infection (orolabial, genital or anorectal of more than one months duration) Esophageal candidiasis Extrapulmonary TB Kaposis sarcoma Central nervous system (CNS) toxoplasmosis 58 HIV encephalopathy WHO Stage IV (2) Conditions where confirmatory diagnostic testing is necessary: Extrapulmonary cryptococcosis including meningitis Disseminated nontuberculous mycobacteria

infection Progressive multifocal leukoencephalopathy (PML) Candida of trachea, bronchi or lungs Cryptosporidiosis Isosporiasis 59 Visceral herpes simplex infection WHO Stage IV (3) Conditions where confirmatory diagnostic testing is necessary: Cytomegalovirus (CMV) infection (retinitis or of an organ other than liver, spleen or lymph nodes)

Any disseminated mycosis (e.g. histoplasmosis, coccidiomycosis, penicilliosis) Recurrent nontyphoidal salmonella septicemia Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Visceral leishmaniasis 60 Severe Chronic Herpes Simplex Ulcers 61 Slice of Life and Suzanne S. Stensaas Disseminated Cutaneous

Cryptococcosis 62 Courtesy of Samuel Anderson, MD Disseminated cutaneous cryptococcosis (2) 63 Courtesy of Samuel Anderson, MD Laboratory Diagnosis of HIV Infection Methods

utilized to detect: Antibody Antigen Viral nucleic acid Virus in culture Laboratory Diagnosis Serology is the usual method for diagnosing HIV infection. Serological tests can be divided into screening and confirmatory assays.

Screening assays should be as sensitive whereas confirmatory assays should be as specific as possible. Screening assays EIAs are the most frequently used screening assays. The sensitivity and specificity of the presently available commercial systems now approaches 100% but false positive and negative reactions occur. Some assays have problems in detecting HIV-1 subtype O. -

- ELISA for HIV antibody Microplate ELISA for HIV antibody: colored wells indicate reactivity Confirmatory assays - Western blot is regarded as the gold standard for serological diagnosis. - However, its sensitivity is lower than screening

EIAs. - Line immunoassays incorporate various HIV antigens on nitrocellulose strips. - The interpretation of results is similar to Western blot. It is more sensitive and specific. Western Blot Most popular confirmatory test.

Utilizes a lysate prepared from HIV virus. The lysate is electrophoresed to separate out the HIV proteins (antigens). The paper is cut into strips and reacted with test sera. After incubation and washing anti-antibody tagged with radioisotope or enzyme is added. Specific bands form where antibody has reacted with different antigens. Most critical reagent of test is purest quality HIV antigen. The following antigens must be present: p17, p24, p31, gp41, p51, p55, p66, gp120 and gp160. Antibodies

Western Blot to p24 and p55 appear earliest but decrease or become undetectable. Antibodies to gp31, gp41, gp 120, and gp160 appear later but are present throughout all stages of the disease. Interpretation of results. No bands, negative. In order to be interpreted as positive a minimum of 3 bands directed against the following antigens must be present: p24, p31, gp41 or gp120/160. CDC

criteria require 2 bands of the following: p24, gp41 or gp120/160. Western blot for HIV antibody There are different criteria for the interpretation of HIV Western blot results e.g. CDC, WHO, American Red Cross. The most important antibodies are those

against the envelope glycoproteins gp120, gp160, and gp41 p24 antibody is usually present but may be absent in the later stages of HIV infection Other diagnostic assays It normally takes 4-6 weeks before HIV-antibody appears following exposure.

A diagnosis of HIV infection may be made earlier by the detection of HIV antigen, pro-DNA, and RNA. However, there are very few circumstances when this is justified e.g. diagnosis of HIV infection in babies born to HIV-infected mothers. Prognostic tests Once a diagnosis of HIV infection had been made, it is

important to monitor the patient regularly for signs of disease progression and response to antiviral chemotherapy. HIV Antigen tests - They were widely used as prognostic assays. - It was soon apparent that detection of HIV p24 antigen was not as good as serial CD4 counts. -The use of HIV p24 antigen assays for prognosis has now been superseded by HIV-RNA assays. HIV Viral Load - HIV viral load in serum may be measured by assays which detect HIV-RNA e.g. RT-PCR, NASBA, or bDNA. - HIV viral load has now been established as having good prognostic value, and in monitoring response

to antiviral chemotherapy. Epidemiology During the first 8 years of the epidemic (1981-1989), 100.000 cases occurred in USA, and the next 100.000 occurred over the subsequent 26 months. The increase in cases continued until the mid 1990s reaching a plateau in 1994. By

the end of 1996, there were 581249 cases with 362004 deaths. Two attributes make AIDS unique among infectious diseases: it is uniformly fatal, and most of its devastating symptoms are not caused by the causative agent. Sexual transmission homosexuals constitute the largest risk group - Male in N. America and Western Europe. developing countries, heterosexual spread - Inconstitute the most important means of transmission.

- Blood/Blood Products Blood and blood product are no more important in most countries due to screening for HIV Haemophiliacs were one of the first risk groups to be identified: they were infected through contaminated factor VIII. IV drug abusers represent the second largest AIDS patient groups in the US and Europe. Vertical Transmission The transmission rate from mother to the newborn varies from around 15% in Western Europe to up to 50% in Africa.

Vertical transmission may occur transplacentally, perinatally during the birth process, or postnatally through breast milk. Current AIDS Statistics At the end of 2011, an estimated 34 million people were living with HIV worldwide, with two-thirds of them living in sub-Saharan Africa. This reflects the continued large number of new HIV infections and a significant expansion of access to antiretroviral therapy, which has helped reduce AIDS-related deaths, especially in more

recent years. The number of people dying of AIDS-related causes fell to 1.7 million in 2011, down from a peak of 2.2 million in the mid-2000s; in 2012 alone 700,000 AIDS related deaths were averted. Adults and Children Living with HIV/AIDS Western Europe 550,000 N. America 1.2 million

Eastern Europe 1 million North Africa 500,000 Caribbean 420,000 Latin America 1.5 million Asia & Pacific 6.6 million Sub-Saharan

Africa 28.5 million Australia & New Zealand 15,000 Total: 40+ million Data from UNAIDS People Living with HIV/AIDS by Region (as % of Total), 2010 East Asia Western/Central Europe 2% North America 4% Central/South America 4%

Eastern Europe/ Central Asia 4% 2% 1% Middle East/North Africa 0.6% Caribbean 0.2% Oceania South/South-East Asia 12%

67% Sub-Saharan Africa Impact on Women Impact Among Children and Young People Half of new HIV infections are among people under 25. More than 90% of children living with HIV

are infected through mother-to-child transmission during pregnancy, around the time of birth, or through breastfeeding. Among young people aged 15-24, young women are more heavily impacted than young men. Children have lost Aged 25+ 50%

Aged < 15 14% Aged 15-24 36% New Infections = 2.7 million Key Points About the Global Epidemic Global pandemic HIV/AIDS is found throughout the world, in every region Earlier

projections were surpassed. HIV/AIDS is on track to be the worst epidemic in history We may still be in the epidemics early phase HIV/AIDS is really multiple epidemics (different populations, levels, regions) Key Points Continued

Certain populations are at particular risk like; youth, women, men who have sex with men, and injection drug users, but the epidemic is generalized in many countries Hardest hit countries are least equipped to respond Multi- sectoral impact, collateral effects:

development and economic growth, education, food supply, communities, Challenges to Addressing the Epidemic Many lack basic information about HIV/AIDS Most people in low- and middle-income countries do not have access to key prevention and care services

Lack of infrastructure, training, quality & monitoring systems, facilities etc. may impede access; other barriers include price, patent laws and other regulatory issues; and the impact of the epidemic on the health sector and health care workers Challenges continued Collateral effects of the epidemic (epidemic exacerbates existing problems and vice versa) There

are promising research directions microbicides, vaccines but a vaccine is still years away Resources$$$ Resource Needs to Address Epidemic in Hard Hit Countries NEED & AVAILABLE FUNDING UNAIDS estimated that approximately $12 billion was needed in 2004, to effectively respond in resource poor settings, climbing to $20 billion annually by 2007 2004 global spending estimated at approximately $6.1 billion

KEY INITIATIVES The Global Fund to Fight AIDS, Tuberculosis, and Malaria has received $6.0 billion in pledges through 2008* Presidents Emergency Plan for AIDS Relief (PEPFAR) World Health Organizations 3x5 Initiative *Pledges as of March 1, 2005; Sources: UNAIDS, AIDS Epidemic Update, December 2004; Global Fund, 2005; WHO. Prevention The risk of contracting HIV increases with the number of

sexual partners. A change in the lifestyle would obviously reduce the risk. The spread of HIV through blood transfusion and blood products had virtually been eliminated since the introduction of blood donor screening in many countries. AZT had been shown to be effective in preventing transmission of HIV from the mother to the fetus. The

incidence of HIV infection in the baby was reduced by twothirds. The management of health care workers exposed to HIV through inoculation accidents is controversial. Anti-viral prophylaxis had been shown to be of some benefit but it is uncertain what is the optimal regimen. Vaccines are being developed at present but progress is hampered by the high variability of HIV. Clinical trials for several vaccines are in progress.

Access to Prevention Access to prevention services remains limited. Most people with HIV are unaware of status Only half of pregnant women with HIV received treatment Reaching populations at higher risk remains challenging There have been successful prevention efforts in different parts of the world. Effective prevention strategies include behavior change programs, condoms, HIV testing, blood supply safety, harm reduction efforts for people who inject drugs, and male circumcision. Experts recommend that prevention be based on knowing your epidemic. Recent scientific studies have shown promising results for several interventions that, when used correctly, may reduce the likelihood of HIV infection or transmission:

Microbicides Pre-exposure prophylaxis Treatment as prevention H.A.A.R.T. Highly Active AntiRetroviral Therapy Access to Treatment More than 14 million people are estimated to be in need of treatment with antiretrovirals (ARVs), but less than half are on treatment.

Percent on ARVs as of the end of 2009 (of those in need of antiretroviral treatment in low- and middle-income countries)

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