CD4 count

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CD4 Count:

CD4 Count By Dr Shashidhar Patil SR, Critical Care Medicine SJMCH, Bangalore

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HIV/AIDS What is CD4/CD8 In  molecular biology ,  CD4  ( cluster of differentiation  4) is a  glycoprotein  found on the surface of immune cells such as  T helper cells , monocytes ,  macrophages , and  dendritic cells . It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody  that reacted with it) before being named CD4 in 1984 .  In humans, the CD4 protein is encoded by the  CD4   gene

Viral Attack on CD4:

Viral Attack on CD4 Attachment (First Step) Surface protein on virus attaches to specific receptor (s) on cell surface Virus specific receptor is necessary but not sufficient for viruses to infect cells and complete replication cycle

Viral Receptors:

Viral Receptors Adenovirus Coxsackie virus Echovirus Epstein-Barr Virus HIV-1, HIV-2 Measles virus Parvo virus, Poliovirus CAR CAR, CD55 Integrin VLA-2, CD55 CD21 CD4, CCR5, CXCR4 CD46 Erythrocyte P Ag

HIV Cell Binding and Entry:

HIV Cell Binding and Entry CD4 Cell R5 HIV CCR5 CXCR4 CD4 T HELPER CD4 CELL

CCR5 Natural Ligand - Chemochines:

CCR5 Natural Ligand - Chemochines T HELPER CD4 CELL CD4 Cell R5 HIV CCR5 CXCR4 CD4 T HELPER CD4 CELL Chemochines Rantes MIP-1 Beta MIP-1 Alpha

HIV Cell Binding and Entry:


SDF-1 - Natural Ligand For CXCR4:


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Innate Immunity Acquired Immunity Retro-viral attachment to CCR5

HIV attacking CD4 cell:

HIV attacking CD4 cell

Viral Replication:

Viral Replication Penetration (Second Step) Enveloped viruses penetrate cells through fusion of viral envelope with host cell membrane May or may not involve receptor mediated endocytosis Non enveloped viruses penetrate by - Receptor mediated endocytosis Translocation of the virion across the host cell

Viral Replication:

Viral Replication Multiplication (Third Step) Replication of viral RNA occurs This utilizes the DNA of host nucleus Invaded CD4 cells genome is altered They produce thousands of copies of HIV- RNA

EM photo of CD4 with HIV infection:

EM photo of CD4 with HIV infection

Viral Replication:

Viral Replication Destruction (Fourth Step) CD4 cells are over powered and destroyed Instead of being defense machinery they Are the seat of HIV replication CD4 cells are destroyed – cytolysis HIV copies are released to attack more CD4

New HIV Budding from CD4:

New HIV Budding from CD4

HIV Life Cycle in CD4 Cell:

HIV Life Cycle in CD4 Cell

CD4 Cell Destruction:

CD4 Cell Destruction

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HIV RNA HIV DNA HIV Nucleus Host Cell Non-Nucleoside RTI Protease Inhibitors Nucleoside Analogue RTI RT Entry Inhibitors HIV: Antiretroviral Therapy

HIV in CD4:

HIV in CD4 HIV is a retrovirus that uses its RNA and the host’s DNA to make viral copy. It has a long incubation period. HIV consists of a cylindrical center surrounded by a sphere-shaped lipid envelope. The center consists of two single strands of RNA HIV causes severe damage to and eventually destroys the immune system by utilizing the DNA of CD4+ lymphocytes to replicate itself, destroying the CD4+ lymphocyte.

HIV Life Cycle - Phases:

HIV Life Cycle - Phases 1. Attachment Reverse Transcriptions Act Here 2. Entry 3. Transcription 4. Integration 5. Polyprotein Production 6. Release 7. Maturation Protein Inhibitors Act Here Phases: binding and entry, reverse transcription, replication, budding, and maturation

HIV Attack :

HIV Attack Host cells infected with HIV have a very short lifespan. HIV continuously uses new host cells to replicate itself. Up to 10 million individual viruses are produced daily. During the first 24 hours after exposure, the virus attacks or is captured by dendritic cells (type of phagocyte) in mucous membranes and skin. Within five days of exposure, infected cells make their way to lymph nodes and then to the peripheral blood, where viral replication becomes very rapid.

CD4 counts:

CD4 counts Number of CD4 cells in blood provides a measure of immune system damage CD4 count reflects phase of disease CD4 count: 500 – 1200: Normal 200 – 500: Beginning of HIV illness < 200: AIDS

Adult CD4 counts:

Adult CD4 counts

Normal CD4 Counts in Children:

Normal CD4 Counts in Children Normal CD4 counts in children vary widely by age. In children less than 5 years of age, instead of measuring the number of CD4 cells ,CD4 percentage (%) is used to determine how much damage has been done to the immune system

Use of CD4 Cell Levels to Guide Therapy Decisions:

Use of CD4 Cell Levels to Guide Therapy Decisions CD4 count The major indicator of immune function Most recent CD4 count is best predictor of disease progression CD4 count usually is the most important consideration in decision to start ART Important in determining response to ART Adequate response: CD4 increase 100-150 cells/µL per year CD4 monitoring Check at baseline (x2) and at least every 3-6 months

Indications for ART :

Indications for ART Treat all (regardless of CD4 count): Pregnant women To treat maternal infection and reduce risk of perinatal transmission HIV-associated nephropathy (HIVAN) Not clearly related to CD4 decline; ART may preserve renal function HBV coinfection , if HBV treatment is needed If ART is not started, HBV therapy should not include agents that may select for resistance to ARVs

Indications for Initiating ART: Chronic Infection:

Indications for Initiating ART: Chronic Infection Clinical Category and/or CD4 Count Recommendation History of AIDS-defining illness CD4 count of <350 cells/µL Pregnant women HIV-associated nephropathy Hepatitis B coinfection, when HBV treatment is indicated* Initiate ART * Treatment with fully suppressive drugs active against both HIV and HBV is recommended.

Indications for Initiating ART: Chronic Infection :

Indications for Initiating ART: Chronic Infection Clinical Category and/or CD4 Count Recommendation CD4 count of >350 cells/µL , asymptomatic, without conditions listed above Optimal time to initiate ART is not well defined; consider individual patient characteristics and comorbidities

Frequency of CD4 Count Monitoring.:

Frequency of CD4 Count Monitoring. ART now is recommended for all HIV-infected patients . In untreated patients, CD4 counts should be monitored every 3 to 6 months to determine the urgency of ART initiation . In patients on ART, the CD4 count is used to assess the immunologic response to ART and the need for initiation or discontinuation of prophylaxis for opportunistic infections

Factors that affect absolute CD4 count.:

Factors that affect absolute CD4 count. The absolute CD4 count is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4+ T lymphocytes Splenectomy or co-infection with human T- lymphotropic virus type I (HTLV-1)8 may cause misleadingly elevated absolute CD4 counts. Alpha-interferon , on the other hand, may reduce the absolute CD4 count without changing the CD4 percentage.9 In all these cases, CD4 percentage remains stable and may be a more appropriate parameter to assess the patient’s immune function.

Idiopathic CD4 lymphocytopenia::

Idiopathic CD4 lymphocytopenia : ICL is defined by a documented absolute CD4 T lymphocyte count of less than 300 cells per cubic millimeter or of less than 20% of total T cells on more than one occasion, usually 2 to 3 months apart, without evidence of HIV infection or any defined immunodeficiency or therapy associated with depressed levels of CD4 T cells . The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defi ned . The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals.

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Cryptococcal and non- tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence.

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The etiology of ICL is unknown . Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration . New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome

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The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring . In selected patients with life-threatening infections or profound immunodeficiency , strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation .

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The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. Low CD8 numbers (< 180/mm3) and the degree of CD4 T-cell activation as measured by HLA-DR expression have been associated with an adverse outcome, namely opportunistic infection-related death .

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Lymphocytopenia is typically not progressive, and in some instances CD4 numbers can return to normal levels in the follow-up period for reasons that are unclear.

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Ref: WHO CONSOLIDATED GUIDELINES on the use of ANTIRETROVIRAL DRUGS FOR TREATING AND PREVENTING HIV INFECTION – J une 2013 Zonios et al . Arthritis Research & Therapy 2012, 14:222 http :// 3. Idiopathic CD4 +   lymphocytopenia : natural history and prognostic factors http :// THANK YOU

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